Mitochondrial damage‐associated molecular patterns: A new insight into metabolic inflammation in type 2 diabetes mellitus

The pathogenesis of diabetes is accompanied by increased levels of inflammatory factors, also known as “metabolic inflammation”, which runs through the whole process of the occurrence and development of the disease. Mitochondria, as the key site of glucose and lipid metabolism, is often accompanied by mitochondrial function damage in type 2 diabetes mellitus (T2DM). Damaged mitochondria release pro‐inflammatory factors through damage‐related molecular patterns that activate inflammation pathways and reactions to oxidative stress, further aggravate metabolic disorders, and form a vicious circle. Currently, the pathogenesis of diabetes is still unclear, and clinical treatment focuses primarily on symptomatic intervention of the internal environment of disorders of glucose and lipid metabolism with limited clinical efficacy. The proinflammatory effect of mitochondrial damage‐associated molecular pattern (mtDAMP) in T2DM provides a new research direction for exploring the pathogenesis and intervention targets of T2DM. Therefore, this review covers the most recent findings on the molecular mechanism and related signalling cascades of inflammation caused by mtDAMP in T2DM and discusses its pathogenic role of it in the pathological process of T2DM to search potential intervention targets.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterised by abnormally high glucose and lipid levels in the blood. 1 When T2DM is not controlled well, it often causes damage to the heart, kidneys, and liver, and mortality is high. 2 T2DM is currently widely considered to be a chronic inflammation disease. 3Abnormally elevated free fatty acids are considered markers of insulin resistance and T2DM. 4,5The overload of free fatty acids may induce the release of proinflammatory factors and stimulate the pancreatic inflammatory response. 6,7High sugar levels and abundance of free fatty acids can further encourage the release of cytokines and chemokines that promote inflammation, 6,8 recruiting more macrophages to islets, and forming a vicious cycle that ultimately prolongs inflammation.0][11] Inflammatory reactions can establish causal relationships with the appearance of T2DM. 124][15] They are important in the control of inflammatory responses to oxidative stress both inside and outside cells 16 and are identified by pattern recognition receptors, formyl peptide receptors (FPRs), and Tolllike receptors (TLRs), 17,18 which induces the appearance of diabetes and its complications. 19For example, the release of mtDNA into plasma can accelerate the development of chronic inflammation in diabetes by inhibiting Glutathione S-transferase kappa one or activating the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. 20,21In addition, inflammation can also lead to imbalance and overall downregulation of mitochondrial dynamics. 22,23[26] Numerous studies conducted in recent years have demonstrated the beneficial effects of mtDAMP intervention, including antiinflammatory, mitochondrial repair, and energy metabolism.For example, by intervening in the mtDNA inflammatory transduction pathway, the cyclic GMP-AMP synthase (cGAS)/cGAMP/STING pathway, 27 it can reduce its inflammatory damage and intervene in metabolic diseases, such as T2DM and insulin resistance. 28In homozygous transgenic mice, overexpression of TFAM can induce high brown adipocyte activation and boost the expression of oxidative phosphorylation, which results in resistance to obesity, 29 suggesting that promoting TFAM expression can help increase energy consumption and provide new ways to treat T2DM.Early studies found that increasing the number of TFAM can stimulate the expression of mtDNA, maintain the structure of mtDNA, promote mitochondrial transcription, 30,31 and create conditions for mitochondrial repair and proliferation, while the quality of mitochondria plays a key role in energy metabolism and cell homoeostasis.Therefore, it can be speculated that either interfering with the expression of mtDAMPs molecules, regulating the conduction of its downstream inflammatory pathways, or regulating the number of its upstream regulators, can interfere with the glucose and lipid metabolism and inflammation level of T2DM, offering a fresh approach to treat T2DM.However, it is still unknown how mtDAMP causes inflammation in T2DM, and more research should be conducted on how mtDAMP affects T2DM's oxidative stress, inflammation, and mitochondrial damage.Therefore, we summarised the relationship between mtDAMP and inflammation in T2DM and explored the pro-inflammatory mechanism and potential intervention targets of mtDAMP in the chronic inflammatory state of T2DM.

| MITOCHONDRIAL DAMAGE-ASSOCIATED MOLECULAR PATTERN
DAMPs from mitochondria mainly include mtDNA, CL, TFAM, Cytc, ATP and N-formyl peptide (NFP).In this part, we summarise and analyse the expression of mtDAMPs and their role in tissue and cell energy metabolism (Table 1) to find their key regulatory factors and downstream targets and provide a reference value for clinical intervention.

| Mitochondrial DNA
Other than the nucleus, mitochondria are the only organelle that has its own DNA, which houses around 37 essential gene codes. 50tochondria have a significant capacity to repair DNA and eliminate poorly functioning mitochondria.However, because of its lack of chromosomes and histon protection, mtDNA is susceptible to oxidation damage.From the mitochondria to the cytoplasm and from the cytoplasm to the extracellular environment are the two phases of the release of mitochondrial mtDNA.Under the influence of reactive oxygen species (ROS) and NOD-like receptor thermal protein domain associated protein 3 (NALP3) inflammasome, the permeability transition pore (mPTP) in mitochondria opens up more, and the VDAC, a regulation protein of the mPTP, interacts directly with mtDNA and enters the cytoplasm 51,52 to complete the first release stage.Furthermore, oxidative stress causes mtDNA to break and facilitates its leaking. 53 is thought that mtDNA is crucial for cell inflammation responses. 546][57] In particular, abnormal mtDNA packaging promotes its release to cells, which binds to cyclic GMP-AMP synthetase (cGAS), and promotes signalling dependent on STING-IRF4, enhancing the type I interferon response. 56Interestingly, mtDNA released from mitochondria also simultaneously activates the proapoptotic caspase pathway and inhibits the inflammatory response produced by type I interferons. 55,58[57] Extracellular mtDNA can stimulate immune cell trafficking, activate neutrophils 59,60 and vascular endothelial cells, and cause inflammation in distant tissues.Mitochondrial DNA can directly produce inflammation and cause tissue damage, for example, mtDNA injections into mice cause lung injury 61 and arthritis with mononuclear cell infiltration. 62The inflammasome is another mediator that triggers the mtDNA inflammatory response.Inflammasome, such as NLRP3, IL-1, is a multiprotein complex that enhances the inflammatory response by promoting the production and secretion of key cytokines and plays an important role in regulating the inflammatory response and intestinal flora in diabetes. 635][66] mtDNA contains a non-methylated CpG residue island, which is detected by TLR 9 receptors when cell stress causes inflammation. 67Additionally, the lack of histones in mtDNA results in its oxidation.Oxidized mtDNA triggers the inflammatory process by igniting the NLRP3 and NLRC4 (Nucleotide-binding oligomerisation domain, leucine-rich repeat and caspase recruitment domain-containing 4) pathways, which release interleukin-1 (IL-1) and IL-18. 68,69At the same time, inflammasome activation can also lead to mitochondrial damage and mtDNA release, forming a feedback loop through impaired Parkin function and mitophagy. 70[73] The latest study found that the mtDNA expression level of male rats was higher than that of female rats in arterial hypertension rats, 74 so we can speculate that gender may be a potential factor for T A B L E 1 Mitochondria-derived damage-associated molecular pattern.the differential expression of mtDNA.However, whether gender factors affect the expression of other mtDAMPS except mtDNA still needs more experiments to explore.

| Mitochondrial transcription factor A
Mitochondrial transcription factor A is expressed in the nucleus, influences the mitochondria, and is essential for the reproduction and upkeep of mtDNA.Mitochondrial transcription factor A regulates the transfer of RNA, the ribosomal RNA encoded by mtDNA, and the gene transcription process of mitochondrial electron transport chain proteins. 75,76TFAM has ensured the transcription and expression of mitochondrial genes through several channels.On the one hand, TFAM can jointly enhance the mitochondrial transcription process when it specifically binds to mitochondrial RNA polymerase and mitochondrial transcription factors B1 or B2. 77On the other hand, TFAM can nonspecifically bind to random sites on mtDNA, 78,79 enhance mitochondrial chromosome stability and maintenance [78][79][80] and regulate mtDNA copy number. 81However, TFAM overexpression boosted mtDNAwithout affecting mitochondrial biogenesis or the respiratory system's capability. 82This suggests that the TFAM action mechanism on mitochondrial biogenesis and mtDNA regulation may be separated.
The expression of TFAM is regulated by nuclear respiration factor 1 (NRF1).Nuclear respiration factor 1 may coordinate the expression of respiratory components with the mitochondrial transcription system by binding to specific promoters of numerous nuclear genes necessary for mitochondrial respiratory activity. 76,83F1 and TFAM are up-regulated in the nucleus in response to metabolic difficulties that the cellular environment experiences, such as exercise or metabolic changes.This is followed by the translocation of TFAM to the mitochondria and a greater frequency of NRF1 with the TFAM promoter. 84However, activated skeletal muscle triggers a cell signalling cascade 85,86 response that accelerates increased Ca 2þ processing in muscle cells, further improving TFAM and NRF1 protein levels and mitochondrial biogenesis, 87,88 forming a positive feedback regulation.When NRF1 89 is inactivated, TFAM expression is inhibited, suggesting that NRF1 is an important regulatory factor for TFAM under REDOX conditions.
Mitochondrial transcription factor A serves as a link between nuclear and mitochondrial gene expression and can up-regulate nuclear gene expression to support the efficient control of nuclear genes on mitochondrial metabolic process.When TFAM is lacking, retrograde signalling is induced to the nucleus, Serca2a expression from the nucleus 90 is inhibited, and ROS and apoptosis are increased. 91In models of heart failure brought on by Ca 2þ leakage from the endoplasmic reticulum, the Serca2 gene may enhance contractile performance and restore electrical stability. 92This shows that TFAM in the mitochondria instructs the nucleus to produce Serca2a and collaborates with the endoplasmic reticulum to keep Ca 2þ levels stable. 93However, it remains unclear how TFAM in mitochondria regulates nuclear Serca2a transcription.Mitochondrial transcription factor A overexpression can increase nuclear expression of various factors related to the Ca 2þ signalling pathway and glucose metabolism in mouse skeletal muscle, 82 enhance antioxidants, reduce ROS, activate adenosine monophosphate activated protein kinase (AMPK), mitochondrial uncoupling and regulation of membrane potential 82 to cope with the intense changes in the internal environment under energy stress.

| Cardiolipin
5][96] Chemically, CL is composed of four fatty acid chains linked to the skeletal structure of diphosphate glycerol, and is considered essential to optimising mitochondrial structure function. 97CL was shown to be necessary to perform the optimal functions of complexes I, III, IV and V. [98][99][100] Cardiolipin remodelling is a potential cause of mitochondrial dysfunction. 101In humans, phospholipase A2 initiates the CL remodelling process, cracking the acyl chain of CL and producing intermediate monolysin CL 102 .4][105] After the above steps are completed, for assembly, CL must be moved from the inner to the outside mitochondrial membrane, albeit the exact transport process is yet unknown.
7][108] CL molecules contain large amounts of polyunsaturated fatty acids, which are the main targets of ROS attacks.
Cardiolipin also participates in internal and external immune inflammatory processes, participates in the initiation of apoptotic activities, and is required to activate NLRP3 inflammatory enzymes. 109CL migrates from the mitochondrial inner membrane to the mitochondrial outer membrane as a result of damaging signals such as mitochondrial damage and depolarisation, releasing into the cytoplasm. 110Consequently, by activating inflammation, the inflammatory reaction cascade is regulated. 109,1113][114][115][116] It has been shown that externalised CL stimulates phagocyte activity in peripheral immune cells.Balasubramanian et al. 45 found that the extracellular CL produced by mitochondria boosted peripheral macrophages' phagocytic activity by four times.In cells resembling microglia, extracellular CL also inhibits the generation of cytotoxins and pro-inflammatory mediators including tumour necrosis factor, nitric oxide (NO), and ROS. 112Additionally, CL provides a platform for activating the caspase 8 of the outer membrane of the mitochondria and transports it to the mitochondria after activating the receptor of fatty acids. 117,118When caspase 8 is activated, the pro-apoptotic protein Bid is cleaved and translocated to the mitochondrial outer membrane, where it penetrates and compromises the structural integrity of the membrane.

| Cytochrome c
0][121] At steady state, as an electron carrier, it is an important part of mitochondrial energy metabolism. 122When cells (such as apoptosis) are stimulated, mitochondrial Cytc releases increase and interact with the apoptosis protease activator factor-1 in cytoplasm 123 to trigger the mitochondrial apoptotic pathway. 3Cytc reaches the core when DNA damage occurs, sequestering histone chaperones and preventing the remodelling of the chromatin 124,125 .
Cytc causes cell death by stimulating oxidative stress and inflammatory reactions.Under nitro-oxidative stress conditions, Cytc, as an inducer of programmed cell death, 126 can promote ROS production and activate oxidative stress through the P66 REDOX cycle.
Cytc nitrified by peroxynitrite ions can also trigger inflammatory processes. 127TLR4 may be activated by the release of Cytc from mitochondria into the cytoplasm, according to recent findings, 128 effectively trigger the inflammatory response, and eventually lead to programmed cell death. 129,130During apoptosis, CL is transferred from the mitochondrial inner membrane to the mitochondrial outer membrane, 129,131 forming the Cytc/CL complex, which is able to catalyze the oxygen-dependent peroxidation of the substrate, 132 leading to an increase in oxidised CL. 133 Inositol 1,4, 5-triphosphate receptors and voltage-dependent anion channels interact with Cytc to induce calcium export and import, respectively, in the early phases of apoptosis, [134][135][136] regulating mitochondrial-endoplasmic reticulum contacts.Note that Cytc released into the cell liquid does not necessarily lead to cell death. 137,138

| Adenosine triphosphate and N-formyl peptide
Adenosine triphosphate is a respiratory product that provides energy for a variety of biological reactions and maintains cell homoeostasis.
Cell stress increases energy demand and causes a rapid change in ATP levels.Adenosine triphosphate is absorbed into the extracellular environment and activates purine receptors and triggers inflammation reaction. 139,140ATP-activated P2Y2R induces the activation of inflammasomes through oxidised low density lipoprotein through mitochondrial damage in human endothelial cells. 1413][144] ATP also affects monocytes and macrophages, promotes the activation of inflammasome, and accelerates the fusion of phagocytes with lysosomes. 145Ps bind formyl groups to methionine and are one of the proteins required to initiate the mitochondrial translation.NFP has a variety of immune functions. 146NFP is highly immunogenic and can be recognized by FPRs present in phagocytes. 17NFP was originally thought to promote neutrophil aggregation and have immunomodulatory effects. 147Subsequent studies have shown that during cell necrosis, to draw and get rid of necrotic cells, NFP may be delivered into the extracellular environment as a chemical agent.The mechanism of NFP-induced chemotaxis is mediated by an increase in Ca2þ influx through FPR. 148When peptides are formed, their functions include morphological polarization, movement, ROS production, and release of protein lytic enzymes. 146NFP also increases its immunechemotaxis by promoting IL-8 release. 149Importantly, NFPs are selectively secreted from necrotic cells, making their action as DAMP more selective with respect to disease pathology. 150

| ROLES OF MTDAMPS AND MITOCHONDRIAL DAMAGE IN TYPE 2 DIABETES MELLITUS
Type 2 diabetes mellitus is characterised by insulin resistance and eventually leads to pancreatic β-cell failure.The inflammasome is spontaneously activated by a mitochondrial ROS burst as a result of cellular responses to oxidative stress risk and buildup of mtDNA, 51 inducing chronic inflammation. 151Mitochondria are the targets and inducers of the inflammatory reaction. 56Early studies 152,153 have elaborated that mtDAMPs are widely involved in the occurrence and development of human diseases, such as cardiovascular disease and cancer, but its pathogenesis in T2DM is not completely clear.
Therefore, we summarised the latest research progress of mtDAMPs in T2DM.In Figure 1, we summarise the possible pathogenic pathways of mtDAMP in T2DM.

| β cell dysfunction
In diabetes, high chronic demand causes endoplasmic reticulum stress and subsequent inflammation. 1546][157] Inflammatory cytokines trigger the key mitophagy processes, such as mitochondrial membrane potential dissipation, Parkin-mediated mitochondrial translocation, and the placement of mitochondria in lysosomes for destruction. 158This can lead to impaired bioenergetics, a decrease in the secretion of glucose-stimulated insulin secretion, and activation of apoptosis. 159 the pathogenesis of T2DM, the main cause of pancreatic β cell failure is mitochondrial dysfunction. 26,160,161The plasma β-cell mitochondria in patients show ultrastructured morphological and functional abnormalities that lead to reduced ATP production and glucosestimulated insulin secretion. 162,163The overproduction of free radicals such as nitrogen oxides and ROSs may cause inflammation to β cells. 164ronic inflammation and the declines in mitochondrial efficiency secretion, as well as impaired glucose absorption and signalling.
However, the exact pathophysiology of mtDNA mutations that lead to diabetes and associated diseases has not yet been fully studied.Small non-coding microRNAs can also influence the mitochondrial gene expression and are useful in the study and treatment of diabetes cardiomyopathy. 165Therefore, mutations in mtDNA in diabetic populations can be further investigated using miRNA.
In order to avoid sterile inflammatory reactions brought on by mislocalisation of mtDNA and activation of DNA sensors, it is crucial to maintain mitochondrial dynamics. 166To get mtDNA closer to TLR9, intimate interaction between the mitochondria and the early endosomes is required. 166Moreover, the mtDNA of the endosomal location can induce an inflammatory pathway of the nuclear factor-kgene binding (NF-kB) nuclear factor dependent on TLR9. 167However, cytoplasmic mtDNA can participate in cGAS 56 or inflammasomes. 168,169Binding of mtDNA with inflammation molecules containing NLRP3 is crucial for the activation of inflammation molecules, 51,170 such as maturation and secretion 66,171 of IL-1β and IL-18 in immune cells.One of the primary pro-inflammatory mediators in chronic T2DM inflammation is IL-1β, 172 which may impair insulin transmission in cells with high insulin sensitivity.Furthermore, local macrophages may detect beta-cell activity by reacting to ATP released by β-cells when combined with insulin, which leads to macrophage activation and inflammation reactions. 173cent research has shown that mtDNA may cause inflammation by triggering the cGAS/STING pathway, which in turn triggers the NF-jB and interferon regulating factor 3 pathways. 174,175Interestingly, p53 is both a tumour suppressor and a glucose metabolism regulator. 176Recent studies have shown that P53 can interact directly with parkin and reduce β-cell mitophagy and inhibit insulin secretion under high glucose conditions, 177 suggesting that cancer, diabetes and inflammation may be inextricably linked in some way.

| Adipocyte
White fat mainly stores excess energy, while brown fat is mainly responsible for energy consumption through non-quivering heat production in mitochondria.Under physiological conditions, adipocytes transfer mitochondria to macrophages in white and brown adipose tissue 178,179 and rely on heparin sulphate 180 to maintain metabolic homoeostasis.When the body is in a state of obesity, the level of heparan sulphate in macrophages in white adipose tissue decreases, leading to a decrease in mitochondrial uptake by macrophages in cytoplasm 180 and a rapid increase in mitochondria from fat cells in circulation, 178 which reduces energy consumption and increases the quality of white adipose tissue.Mitochondrial dysfunction has been reported to adversely affect adipocyte differentiation, lipid metabolism, insulin sensitivity, oxidation capacity, and thermogenesis, leading to metabolic diseases, including obesity and T2DM. 181ite fat cells have more mitochondria than brown fat cells, which can turn brown under certain circumstances and provide energy for the body.However, brown adipocyte albinism can lead to abnormalities in endoplasmic reticulum structure, autophagy, mitochondrial degeneration, increased collagen fibres, large monocular lipid droplet accumulation and other lesions, which are associated with mitochondrial dysfunction, strong inflammatory response, and activation of NLRP3 inflammasome, which may lead to the typical inflammatory state common in obesity. 182,183Chronic fat tissue inflammation is an important risk factor for insulin resistance and T2DM in overweight people. 184The increase in fat tissue in obese patients is the result of an increase in the number and size of adipocytes, 185 which can result in hypoxia.Continuous cell hypoxia leads to mitochondrial respiratory dysfunction, overproduction of ROS, reduced production of ATP, as well as accumulation of mtDNA mutations. 186,187Inflammatory cytokines lead to decreased mRNA expression of mitochondrial key transcription factors and control proteins in adipocytes, including PGC-1α (peroxisome proliIeratorsactivated receptor γ coactivator lalpha) and eNOS, and the death of COX IV and Cytc expressions. 188 fat tissues, macrophages are damaged by oxidation and have a tendency to develop metabolic diseases.Macrophages have antiinflammatory effects in the lean adipose tissue, and their role is comparable to that of M2-type macrophages, which may keep the environment in adipose tissue in balance. 189While in obese adipose tissue, macrophages are similar to M1-type macrophages, that change leads to increased pro-inflammatory cytokine, and insulin resistance.Increased glucose consumption in M1 macrophages is linked to cytokine synthesis that occurs quickly and an increase in the antibacterial activity of ROS. 1902][193][194] The TCA cycle is still active and connected to oxidative phosphorylation in M2 macrophages. 191 The immune system's inflammatory response, glycolipid metabolism, and fat metabolism are all significantly affected by NLRP3. 195t acids promote mtROS production by activating NLRP3 in macrophages and by activating macrophage inflammation. 196In addition to decreasing insulin sensitivity, activated NLRP3 encourages the release of IL-1β, which has a paracrine effect on the immune system of adipose tissue.Inhibition of NLRP3 inflammasomes can reduce IL-1β and the level of inflammatory stress, eventually slowing the development of T2DM. 197

| Skeletal muscle
Muscle mass is a critical factor in glycometabolism and has a negative correlation with insulin resistance. 198,199Reduced glucose absorption in skeletal muscles, together with abnormalities in insulin signalling, oxidative phosphorylation, and glycogen formation, are signs of insulin resistance. 200The muscles of the skeleton play a central role in the insulin resistance of the entire body. 201Abnormal mitochondrial fission was found to be causally related to mitochondrial dysfunction and insulin resistance in skeletal muscle of genetically obese mice and diet-related obese mice, while inhibition of mitochondrial fission improved muscle insulin signalling and systemic insulin sensitivity in obese mice. 202Therefore, the disruption of mitochondrial dynamics may be the basis of the pathogenesis of muscle insulin resistance in obesity and T2DM. 202,203Under normal conditions, the frequency of mitochondrial fusion and fission events is balanced to maintain the overall morphology of mitochondrial populations. 204,205Mitochondrial fusion is regulated by different proteins, including mitofin-1, mitofin-2, and optic atrophy, while fission is controlled by mitochondrial fission 1, dynamic-related protein 1 (Drp1), and mitochondrial fission factor.The lack of fission in down-regulated Drp1 expression leads to loss of mtDNA and decreased mitochondrial respiration. 206e contents of muscle macrophages in the skeleton are negatively and dynamically related to insulin sensitivity. 207,208Inflammatory factors emitted by macrophages induce lipolysis and raise levels of lipid metabolism. 209Chronic inflammation reduces lipogenesis and increases lipolysis in fatty tissues, leading to increased circulation of fat acids and triggering the accumulation of ectopic fats in the skeletal muscle. 210,211Intracellular lipid storage was negatively correlated with insulin resistance, but not in endurance training athletes (the athlete paradox), which may be related to lipid droplet morphology and distribution. 212,213It was found that lipids were mainly stored in large lipid droplets in the submuscular region of type II fibres in patients with T2DM, while training participants stored lipids in more lipid droplets in the intramuscular region of type I fibres.In addition, after endurance training, the lipid droplet phenotype of T2DM patients shifted to an "athlete like" phenotype, with increased lipid droplet turnover related protein content accompanied by improved insulin sensitivity. 213,214This suggests that the morphology and distribution of lipid droplets is a major determinant of skeletal muscle insulin sensitivity.
It was reported that TFAM overexpression in skeletal muscles prevents insulin resistance caused by high fat diets and maintains a high level of mtDNA. 82Increased PGC-1α and peroxisome proliferator-activated receptor levels in the tissue are crucial for reducing T2DM and insulin resistance.Mitochondrial transcription factor A regulates Ca 2þ signalling to the nucleus through mitochondrial status and normal mitochondrial biogenesis through PGC-1α, a signalling pathway that coordinates various transcription factors, including NRF-1 and the activated receptor of the PPARδ.PPARδ regulates the expression of glucose transporter type 4 and glucose uptake in muscle tissue. 215TFAM can also enhance fat oxidation and attenuate insulin resistance 216 induced by a high-fat diet in skeletal muscle by regulating flux and conduction. 217TFAM mutant mice develop diabetes, exhibit mtDNA deletions, oxidative phosphorylation defects and abnormal mitochondrial structures. 88While TFAM overexpression has a protective impact, mitochondrial failure may activate the NAD þ -dependent SIRT1/PGC-1α/TFAM signalling pathway to exacerbate diabetic peripheral neuropathy. 218This shows the potential benefits of TFAM in treating diabetes and its complications.

| Liver
Chronic inflammation causes insulin resistance in the liver. 219,220pogenesis induced by macrophage-derived cytokines causes lipid toxicity, resulting in liver inflammation and insulin resistance. 221though there are few studies on the role of mtDAMPs in hepatic insulin resistance, TFAM and CL-related proteinase show potential therapeutic benefits for reducing insulin resistance to inflammation and liver.Adipose CL synthase one inhibits activating transcription factor 3 expression and activity in the pathological process of non-alcoholic fatty liver disease, thereby improving insulin resistance, inflammation, and fibrosis. 222Studies have shown that the overexpression of specific TFAM in mouse hepatoma can mitigate alcohol-induced mitochondrial dysfunction and liver damage through the NRF-1/TFAM pathway. 223SIRT2 can improve insulin resistance in hepatocytes by increasing the fusion-related protein mitofin-2, reducing Drp1 and attenuating the down-regulation of TFAM to promote increased mitochondrial mass. 224TFAM and adipocytic CL synthesis 1 can be used to treat liver metabolic inflammation.
Studies have shown that compared to the liver of aged rats, the binding of TFAM to mtDNA is reduced and mtDNA damage increases in the liver of very aged rats. 225However, in early experiments, the researchers found that calorie restriction could completely inhibit the age-related decrease in mtDNA and TFAM content by affecting the origin of TFAM binding to mtDNA replication. 226This suggests that excessive caloric intake and ageing may be the underlying causes of aseptic inflammatory liver injury.In the hypoxia-reoxygenation environment, mitochondrial damage and mitophagy function of ageing macrophages increase, which promote cytosolic leakage of mtDNA and enhance STING activation.Mitochondrial DNA deletion or inhibition of cGAS will make STING activation disappear. 227STING deficiency has a protective effect on different types of inflammatory aseptic liver injury.In addition to metabolic stress induced by hypoxia-reoxygenation, other types of oxidative stress and hepatotoxic stress can inhibit mitophagy and promote the cytosolic release of mtDNA, thereby activating STING signalling in ageing macrophages. 227This provides a new potential therapeutic target for aseptic inflammatory liver injury in elderly patients.

| MITOCHONDRIAL TARGETING THERAPY AND PROSPECTS
Treatment strategies for mitochondrial disorders can be developed in several ways: (i) increasing mitochondrial biogenesis; (ii) mitochondrial replacement therapy; (iii) the impact of intervening in mitochondrial dysfunction; and (iv) reprogramming the mitochondrial genome. 158,228Currently, most interventions directed at mitochondrial biogenesis are based on supporting the respiratory chain function (eg.Q10, succinate, thiamine), supplementing antioxidant pools. 229Therefore, we summarised the latest intervention drugs targeting mtDAMP, mitophagy, and the expression of downstream inflammatory pathways (Table 2), in order to find effective intervention targets for mitochondria-mediated chronic inflammation in T2DM.

| Targeting mitochondrial damage-associated molecular pattern
Empagliflozin, an inhibitor of sodium-glucose transport-2 (SGLT2i), relieves the remodelling of the heart and enhances the mitochondrial activity in rats that has been produced by a high-fat diet or streptolutein in diabetic rats, 230 possibly through the PGC-1α/NRF-1/TFAM signalling pathway.Furthermore, engliazine inhibits the number of copies of urinary mtDNA and interleukin-1 in patients with T2DM, minimises mitochondrial damage, and inhibits inflammation reactions. 231It has a direct effect on mitochondrial functions, biogenesis, and membrane potential, improving mitochondrial function and membrane potential. 232The use of SGLT2i may be more beneficial in elderly patients. 249 metabolic analysis, glycolytic metabolic compounds and ATP increase in muscle quickly during inhibition of SGLT2, whereas amino acids and free fatty acids remain unchanged.Glycolytic metabolites were reduced, and amino acids and free fatty acids in slow muscles increased, but ATP remained unchanged. 250This suggests that SGLT2i affects slower and faster muscles differently, but is not affected by impaired glucose metabolism, which provides new information on its use in diabetic patients at high risk of sarcopenia.
In addition, sitagliptin increases the expression of PGC-1/NRF1/ TFAM and promotes mitochondrial biogenesis in human SH-SY5Y cells. 233Ketogenic diets can selectively eliminate heterogeneous mtDNA mutations, increase mtDNA levels, and reduce insulin resistance. 234,235However, these conclusions were confirmed only in vitro and its effectiveness in the complex human environment must be further confirmed.

| Targeting downstream inflammatory pathways
The AMPK/SIRT1/PGC-1α pathways allow for the promotion of mitochondrial biogenesis and function by canagliflozin. 236Canagliflozin also increases mitochondrial oxidation phosphorylation and thermogenesis and induces mitochondrial biogenesis. 236iazolidinedione is an anti-abortic drug targeting PPAR-γ, promoting fat acid storage and inhibiting its production. 237In addition, macrophage M2 is a result of PPAR-γ activation, which lowers insulin resistance. 238Thiazolidinedione has some therapeutic benefits by targeting downstream PPAR-γ inflammatory pathways and promoting the anti-inflammatory effects of the macrophage phenotypic transformation.
An incretin mimic, GLP-1 Ras, is used to treat T2DM and obesity.
Reduced appetite and a lower risk of stroke are two of this medication's active side effects. 251Liraglutide reduces chronic inflammation and decreases mitochondrial stress markers in TNFα and IL-1β in rats 239 and promotes the production of anti-inflammatory molecules. 240However, the systemic effects of glucagon-like peptide-1 (GLP-1) Ras and symptoms of the gastrointestinal tract limit its application. 252,253aditional Chinese medicine has also shown some advantages

| Targeting mitochondrial autophagy
Recent research has shown that metformin improves chronic inflammation by improving metabolic parameters and also has a direct anti-inflammatory effect. 245Metformin can inhibit the activation of NLRP3 inflammasomes and inflammation of fat tissues by maintaining mitochondrial integrity by maintaining drp1 inhibitory activity. 244Metformin is the most widely used drug to treat T2DM, but it has shown that it causes lactic acidosis, so it is not recommended for mitochondrial diabetes. 254 addition, it has been shown that Dapagliflozin improves mitochondrial function by increasing the level of fusion fission control protein, preventing mitochondrial damage, and reducing oxidative stress. 246Hirudin can prevent pancreatic β-cell dysfunction caused by lipotoxic factors by inhibiting the stress of the endoplasmic reticle and excessive autophagy. 247Melatonin can mediate the protective effects of diabetic kidney disease by increasing the AMPK/ SIRT1 axis and improving the health of autophagy and mitochondria. 248Currently, studies on inflammation-mediated inflammation in T2DM are very limited, but it plays an irreplaceable role in the development of disease and may be one of the future research directions.

| Other methods
Studies have found that patients with T2DM after exercise training partially change in an "athlete-like" way, and the LD phenotype partially shifts to an "athlete-like" phenotype accompanied by increased lipid droplet related protein content and increased -9 of 18 insulin sensitivity. 213,214This suggests that adjusting the distribution and morphology of lipid droplets through exercise training is an effective way to improve insulin resistance in T2DM, and it may also have some benefits for improving mitochondrial dysfunction related to abnormal lipid metabolism.In addition, the release of mitochondrial DAMPs was found to be associated with changes in mitochondrial metabolism and increased ROS production, resulting in oxidative modification of DAMPs, 255 further confirming the feasibility of our hypothesis that exercise training may be a potential therapeutic approach to intervene in mtDAMPs-mediated T2DM inflammation.
In recent years, the development of new materials has provided strong support for the optimal efficacy of drugs.For example, extracellular vesicles coated with micro rna are used as immune regulation of novel drug delivery systems, 256 which provides a new idea for our targeted intervention of mtDAMPs.In addition to targeting the expression of related proteins or pathways, can we explore vectors that can target the clearance/absorption of mtDAMPs to reduce the damage of excess inflammatory cytokines?Mitochondrial transplantation, as a novel therapeutic strategy, can be applied to regulate the anti-tumour activity, chemotherapy resistance and mitochondrial dynamics of breast cancer, 257 providing a new opportunity for the treatment of mitochondrial dysfunction diseases. 258wever, to date, these strategies must be further investigated as the levels of mitochondrial gene recoding and mitochondrial transmission technology are limited.
associated with age are in part due to the accumulation of mtDNA mutations.Mitochondrial DNA mutations mainly mediate diabetes in the pancreatic β cells.Mitochondrial DNA mutations result in impaired protein synthesis, impaired ATP production, abnormal insulin WANG ET AL.

F I G U R E 1
Proinflammatory effects of mtDAMPs in T2D.When cell damage or mitochondrial dysfunction occurs, the citric acid cycle is inhibited, fat oxidation is increased, and large amounts of reactive oxygen species (ROS) are released.On the one hand, the burst of ROS can rapidly activate the NF-kB pathway and induce an inflammatory response.On the other hand, ROS can cause secondary damage to mitochondria.Damaged mitochondria release Cardiolipin (CL), adenosine triphosphate (ATP), mitochondrial DNA (mtDNA) and other proinflammatory factors, which activate TLR-9, NLRP3 and cyclic GMP-AMP synthase (cGAS)/STING/TBK1 pathways, respectively, to accelerate the release of inflammatory factors and trigger inflammatory responses.In addition, the large number of intracellular FFAs can induce ER stress, disrupt mitochondria-ER calcium flux, and accelerate the process of cell necrosis.
in inhibiting the inflammatory pathways associated with mtDAMP and protecting β cells.For example, Irisin reduces the inflammatory response and beta-cell insulin resistance brought on by lipotoxin in cells by increasing the PI3K/AKT/FOXO1 (phosphatidylinositol 3-kinase/protein kinase B/forkhead box O) signalling pathway and suppressing the TLR4/NF-kB signalling pathway. 241Sulphated fucogalactan from laminaria japonica ameliorates β-cell failure by attenuating mitochondrial dysfunction via the SIRT1/PGC-1α signalling pathway. 242Preservation of mitochondrial homoeostasis is responsible for the ameliorative effects of the Suhuang antitussive capsule on non-resolving inflammation via inhibition of NF-κB signalling and activation of NLRP3inflammasome activation.243

5 | CONCLUSION Type 2
diabetes mellitus progress is often accompanied by REDOX imbalances and chronic inflammation.Mitochondria are the centres of energy metabolism.In T2DM metabolic disorder microenvironments, high energy requirements can cause structural and functional damage to mitochondria.Damaged mitochondria or dead cells release damage-related molecules called mtDAMP, including mtDNA, ATP, TFAM, CL, and Cytc.Mitochondrial damage-associated molecular pattern initiates and participates in inflammatory processes in and around cells, thereby aggravating metabolic diseases and insulin resistance.Mitochondrial damage-associated molecular pattern may act on β cells, adipocytes, skeletal muscle cells and liver cells, and is widely involved in the inflammatory response in patients with T2DM, eventually leading to insulin resistance and β cell function failure.Due to the difficulty of implementing mitochondrial transplantation and genetic programming technologies to address mitochondrial dysfunction, the current research results are not ideal.Therefore, clinical treatment can be initiated mainly by mtDAMP molecules, downstream inflammation pathways and mitochondrial autophagy.The clinical application of new hypoglycemic agents, such as SGLT-2i and GLP-1 Ras, has shown a certain efficacy.Previous hypoglycemic agents, such as metformin and thiazolidinedione, and some traditional Chinese medicines have also been found to have anti-inflammatory potential in recent studies.However, the clinical use of Ras GLP1 and metformin is limited by side effects and the benefit pool is limited.In the future, with the development of metabonomics and genomics, mitochondrial transfer and gene recoding technology may become a new star in clinical research.AUTHOR CONTRIBUTIONS Yan Wang wrote the main text.Jingwu Wang contributed equally to this work.Si-Yu Tao, Zhengting Liang, Rong xie et al. retrieve and organise the documents.Guangjian Jiang and Deqiang Deng made a great contribution in the second-time revision, polishing the manuscript, and helping in revising figures.Yan Wang is the first author and Jingwu Wang is the co-author.
T A B L E 2