• mitochondria;
  • neurodegenerative diseases;
  • reactive oxygen species


  1. Top of page
  2. Abstract
  3. Introduction: Specific Properties of Neuronal Mitochondria
  4. Neurodegenerative Diseases with Evidence for Direct Mitochondrial Involvement
  5. Genetic Mechanisms Explaining Disease Progression
  6. Final Remarks
  7. Acknowledgements
  8. References

The classical bioenergetical view of the involvement of mitochondria in neurogeneration is based on the fact that mitochondria are the central players of ATP synthesis in neurons and their failure leads to neuronal dysfunction and eventually to cell death. Mutations in at least 39 genes in inherited neurodegenerative disorders seem to alter directly or indirectly mitochondrial function. Most of these mutations do not directly affect oxidative phosphorylation, but act through disturbed mitochondrial dynamics and quality control. This, however, does not invalidate the bioenergetic hypothesis. Neurodegeneration is not necessarily associated with a gross failure of ATP production, but might rather be a consequence of local insufficiencies of ATP supply in critical compartments of neurons, like the presynaptic terminal. We hypothesize that slow disease progression, at least in a subgroup of neurodegenerative diseases, can be explained by the parallel action of subcellular ATP insufficiency and clonal expansion of somatic mitochondrial DNA mutations, and particularly deletions. © 2013 IUBMB Life, 65(3):263–272, 2013

Introduction: Specific Properties of Neuronal Mitochondria

  1. Top of page
  2. Abstract
  3. Introduction: Specific Properties of Neuronal Mitochondria
  4. Neurodegenerative Diseases with Evidence for Direct Mitochondrial Involvement
  5. Genetic Mechanisms Explaining Disease Progression
  6. Final Remarks
  7. Acknowledgements
  8. References

It is a well-known fact that mitochondrial oxidative phosphorylation provides the major source of ATP in neurons. From the classical viewpoint, adequate levels of ATP are essential to maintain the neuronal plasma membrane potential via the sodium–potassium ATPase, which consumes about 40% of the energy (1). In addition, mitochondria are an important intracellular Ca2+ sequestration system (2, 3), and especially synaptic mitochondria are indispensible for neurotransmitter reserve pool mobilization in the presynaptic compartment (4). Due to these important features, mitochondria can modulate neuronal excitability and synaptic transmission (5, 6). In addition, more recent evidence shows that mitochondria in neurons are highly dynamic organelles undergoing extensive fusion, fission, and have sophisticated mechanisms for quality control, which is extremely relevant for a dependable long-lasting function of these postmitotic cells, working in highly specialized networks and being not subject to further selection mechanisms. This review summarizes recent evidence showing the link of dysfunctional mitochondria and progressive neurodegeneration in certain neurodegenerative disorders.

Mitochondrial Dynamics in Neurons

In the neuronal soma, mitochondria undergo extensive fusion and fission events enabling adequate content mixing. The mitofusins, Mfn1 and Mfn2, are located in the outer membrane and are involved in the early events of membrane fusion (7, 8), whereas the dynamin-related protein Opa1 is inner membrane associated and essential for inner membrane fusion (9). Mutations in the MFN2 and OPA1 genes are associated with neurodegenerative diseases—Charcot-Marie-Tooth neuropathy type 2A (CMT2A) and dominant optic atrophy (OA), respectively (10–12). Neurodegeneration appears to be the prominent phenotype in mice with a targeted mutation in MFN2, and cells lacking mitochondrial fusion show a severe defect in their respiratory capacity (13, 14). Particularly, fusion events allow efficient complementation of damaged proteins, DNA and RNA. On the other hand, vesicular mitochondria which are formed as result of fission events from the mitochondrial network are the cargo of axonal transport of mitochondria into the presynaptic compartment (Fig. 1). Here, high ATP requirements result from ion pumps, pumps required for sequestration of neurotransmitters, and ATP-dependent reserve pool vesicle mobilization (4). The anterograde axonal transport of mitochondria along microtubules (Fig. 1) is performed by the action of two cargo adaptor proteins—Miro and Milton, which link mitochondria to kinesin-1 motors in neurons. Miro attaches the mitochondrial outer membrane with the mitochondria-specific adaptor protein Milton, which is directly linked to the kinesin-1 heavy chain (15–17). Additionally to its adaptor function, Miro is a calcium-binding protein (18) and works as sensor for local Ca2+—and ATP—concentrations. In the Ca2+—free state, Miro binds Milton and mitochondria are attached to microtubules and can be transported. At higher Ca2+—concentrations, Miro is unable to bind Milton, and therefore, the cargo mitochondria are detached from the microtubules (19). The specific Ca2+-sensor properties of Miro enable effective mitochondrial transport along microtubules only when the local Ca2+-concentration is low and the ATP concentration is high (20, 21). Mitochondria are cleared from the presynaptic compartment by retrograde transport with the use of dynein motor proteins linked via the adaptor protein dynactin (22). This mechanism ensures sufficient and effective distribution of the ATP producers directly to the sites of high energy consumption to avoid large gradients of adenine nucleotide concentrations. To have sufficient amounts of well functioning, localized ATP producers is essential for large cells and in particular for neurons. That might be one of the major reasons why impairment of mitochondrial dynamics and, consequently, also of axonal transport is one of the most frequent causes for neurodegenerative disorders (see section “Neurodegenerative Diseases with Evidence for Direct Mitochondrial Involvement,” below).

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Figure 1. Scheme illustrating axonal transport and mitochondrial dynamics in neurons. The high energy demand in the presynaptic compartment is illustrated by the orange shading. Intact mitochondria are shown in green, whereas red indicates damaged mitochondria. Miro and Milton are implicated in the specific linkage of mitochondria to the kinesin-1 motor, relevant for anterograde transport (blue symbols). Damaged mitochondria are cleared from the presynaptic compartment in retrograde transport by dynactin linking to a dynein motor (purple symbols). The damaged organelles are either removed by mitophagy or regenerated by content mixing through fusion with intact mitochondria. [Color figure can be viewed in the online issue, which is available at]

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Mitochondrial Quality Control

A relevant aspect of the long-term maintenance of mitochondrial function in postmitotic cells such as neurons is an effective quality control. This issue gained a rapidly increasing interest in the last years. In opposite to fast dividing cells, neurons (integrated in complex networks) cannot be simply eliminated by selection processes if they have compromised mitochondria. Neuronal mitochondria, therefore, need mechanisms to eliminate damaged proteins which occurs, for example, by the AAA (ATPase associated with diverse cellular activities) protease paraplegin (SPG7), which is mutated in hereditary spastic paraplegia (HSP) 7, but also by the paraplegin-related protease AFG3L2, which is mutated in SCA28 (23). Other routes for mitochondrial protein degradation exist also, because outer membrane proteins can be back transported into the cytosol for subsequent clearance by the proteasome with the mitochondrially targeted valosin-containing protein (VCP/p97, also a AAA protease (24)), which is mutated in a specific form of inherited amyotrophic lateral sclerosis (ALS).

In addition to the quality control on the protein level, recent evidence suggests also the operation of a quality control on organelle level. The prerequisite of a functional organelle-level quality control is that neurons must be able to distinguish between “intact” and “damaged” organelles. This distinction is apparently based on the potential of the mitochondrial inner membrane (Δψ) and the rate of generation of reactive oxygen species (ROS). Mitochondria are recognized as “damaged,” if their mitochondrial membrane potential is low due to a dysfunctional respiratory chain and, correspondingly, their generation rate of ROS is high due to the inhibition of electron transfer (see below, section “Mitochondrial Formation of ROS and Neurodegeneration”). These damaged mitochondria are eliminated via selective mitophagy (25) with the involvement of PINK1 and parkin, being mutated in the PARK6 and PARK2 forms of inherited parkinsonism (see section “Neurodegenerative Diseases with Evidence for Direct Mitochondrial Involvement”). However, it is difficult to imagine that disassembly of whole mitochondria is an energetically favorable way of quality control. Rather, different pathways to restore the function of damaged mitochondria probably represent a more economical solution. Such pathways include i) the above mentioned quality control on protein level and ii) homogenization of organellar contents by fusion and fission within the dynamic mitochondrial network (cf. Fig. 1). The mixing of the matrix content of a few damaged mitochondria with the larger matrix pool of the intact mitochondrial network potentially allows an efficient complementation of biomolecules (26). Therefore, effective mitochondrial “content mixing” is able to reduce the deleterious effects of damaged proteins and RNAs and mutated mitochondrial DNAs (mtDNAs) (13, 14, 25). In this aspect, the correct function of mitochondrial quality control and mitochondrial dynamics appear very much interrelated. In case of mtDNA mutations, content mixing might paradoxically contribute to the spread of mutated molecules through attenuating a radical selection against nonfunctional mitochondria.

Mitochondrial Formation of ROS and Neurodegeneration

It is commonly accepted that ROS (H2O2, O2, and OH) play a significant role in pathogenesis of various neurodegenerative diseases (for comprehensive reviews see (27, 28)). Despite the progress in characterizing ROS effects on lipids (resulting in peroxidation), proteins (resulting in SH-group oxidation and formation of carbonyls), and DNA (formation of 8-OH guanosine and of single and double strand breaks) (29, 30), the particular impact of potential sites relevant for cellular superoxide and hydrogen peroxide generation in brain tissue is less clear. Within the respiratory chain complex I, the FMN moiety (31, 32), iron-sulfur clusters (33, 34), and semiquinones (35) have been suggested to be responsible for mitochondrial superoxide production. For respiratory chain complex III, the semiquinone at center “o” of the Q-cycle (being stabilized by antimycin A treatment) has been identified as an additional site of mitochondrial superoxide production (36), which in contrast to complex I releases superoxide to the intermembrane space (37, 38). While under conditions of inhibited electron transfer (e.g., under conditions of cytochrome c release), all these sites are potentially relevant, the relevance of the latter site under the conditions of uninhibited electron flow is still a matter of discussion (39, 40). Additionally to the sites within mitochondrial respiratory chain, several flavoproteins in the mitochondrial matrix space, like the α-lipoamide dehydrogenase moiety of the α-ketoglutarate dehydrogenase complex (41, 42) or the electron transfer flavoprotein of the β-oxidation pathway (37), are further candidate sites for mitochondrial superoxide production.

In brain tissue, apart from the monamine oxidases of outer mitochondrial membrane (involved in catecholamine breakdown (43)), there exist further potentially relevant ROS producers, and many of these are located outside of mitochondria. These are plasma membrane NADPH oxidases that are highly expressed in astrocytes and oligodendrocytes (44, 45), cytochromes P450 (46), and even catecholamine derivatives (47). Thus, elevated rates of basal ROS production by catecholamine metabolism might explain the high loads of mtDNA deletions observed in aged substatia nigra neurons (48, 49). Additionally, oligodendrocytes and astrocytes contain considerable amounts of peroxisomes, which potentially also could contribute to overall physiological ROS production in brain tissue. On the cellular level, astroglial cells are considered to contain much more glutathione than neurons (for review, see (50)), so that the additional ROS producers of astroglial cells might be in general less relevant. Also cultured neurons from the cortex contain considerably less glutathione than astroglial cultures from cortex (51). However, it has been demonstrated that the amount of glutathione in neurons and astroglial cells varies with the brain region from which the cells have been prepared (52), explaining in part the selective vulnerability of certain neuronal populations.

Studies on brain homogenates indicate that ∼60% of estimated maximal ROS production is of mitochondrial origin (40). Under pathological conditions (e.g., in ischemia—reperfusion injury, in inflammation, etc.), this is highly relevant, because interruption of electron flow through mitochondrial respiratory chain (e.g., by cytochrome c release, modification of electron transport proteins) would considerably increase superoxide generation by all relevant single electron donor sites of damaged mitochondria, given enough oxygen is available (32, 40, 53). Thus, pathological conditions strongly facilitating ROS-mediated oxidative damage of proteins, lipids, and DNA would require an effective elimination of damaged proteins but also damaged mitochondria by the quality control machinery discussed above (section “Mitochondrial Quality Control”), in order to avoid further cellular damage.

Specific Properties of Neuronal Cell Populations

As noted above, difference in glutathione content and differences in expression of ROS producing enzymes might already explain differences in vulnerability between neurons and astroglial cells. However, considerable differences occur also between individual neuronal populations. As an example, hippocampal granular cells are much more resistant to seizure-induced damage than pyramidal cells or interneurons (54). Possible reasons are large differences in mitochondrial content—granular cells contain, in contrast to fast-spiking interneurons and principal cells, less mitochondria (55). A higher mitochondrial content is very likely related to stronger dependency on OxPhos-related ATP production. In turn, these cells produce upon an injury higher amounts of respiratory chain-dependent ROS and are, therefore, at much higher risk of cellular damage at insults, which explains their increased vulnerability.

Neurodegenerative Diseases with Evidence for Direct Mitochondrial Involvement

  1. Top of page
  2. Abstract
  3. Introduction: Specific Properties of Neuronal Mitochondria
  4. Neurodegenerative Diseases with Evidence for Direct Mitochondrial Involvement
  5. Genetic Mechanisms Explaining Disease Progression
  6. Final Remarks
  7. Acknowledgements
  8. References

Compelling evidence for the direct involvement of mitochondria in the pathogenesis of neurodegenerative diseases comes from the identification of mutated genes in the inherited forms of these diseases (see Table 1). These include inherited forms of Parkinson's disease (PD), spinocerebellar ataxias (SCA), HSP, CMT, Huntington's disease (HD), ALS, OA, and progressive epilepsy, but not Alzheimer's disease. However, only several rare forms of these neurodegenerative diseases can be classified as direct mitochondrial disorders affecting primarily OxPhos: IOSCA, SCAR9, MIRAS, rare forms of PD, LHON, AHS, MERRF, and MELAS. Apart from maternal inherited forms of progressive myoclonic epilepsy which have been associated with point mutations in mitochondrial tRNA genes ((57); cf. Table 1), only two well proven pathogenic point mutations of mtDNA have been reported to be associated with parkinsonism (58) and spinocerebellar ataxia (59), respectively. One further report, proposing a more general maternal inheritance of neurodegenerative disorders (60), remains to be confirmed by other groups. Nuclear mutations affecting proteins involved in mtDNA replication—the mtDNA polymerase γ (POLG) and the helicase Twinkle (c10orf2)—cause progressive myoclonic epilepsy (61) and rare forms of ataxia (62). Among rare ataxias, two further disorders have been associated directly with oxidative phosphorylation: Friedreich's ataxia, caused by mutations of frataxin involved in the synthesis of iron-sulfur proteins (63) and SCAR9, caused by mutations in ADCK3, a regulatory protein involved in the synthesis pathway of coenzyme Q (64). All other neurodegenerative diseases show only indirect links to OxPhos, because they affect mitochondrial dynamics (CMT2A, OPA1, and OPA3) or quality control (SCA28, SPG7, PARK2, PARK6, and PARK7) or related pathways. Therefore, taken together, neurodegenerative disorders cannot be simply classified as mitochondrial cytopathies. Nevertheless, it is important to mention in this respect that among the about 100 identified genes so far associated with inherited forms of neurodegenerative disorders, at least 39 have some type of association to mitochondrial function (Table 1). These genes either code for proteins in known mitochondrial biochemical pathways or mitochondrial structural proteins (27 genes) or for proteins that are not necessarily targeted to mitochondria, but that affect them secondarily, like those involved in the communication between mitochondria and the ER or involved in mitophagy (12 genes; cf. comprehensive review by (56); and Table 1).

Table 1. Mitochondrial or interacting with mitochondria genes associated with inherited neurodegenerative diseases (modified according to ref.56)
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Among neurodegenerative diseases, especially genetic forms of PD appear to be closely related to impairment of mitochondrial quality control. Recent evidence strongly suggests that parkin, a cytosolic E3 ubiquitin ligase, which is mutated in PARK2, recruits damaged mitochondria by its direct interaction with PINK1 (65, 66) thus initiating their elimination. Accordingly, loss-of-function PINK1 mutations have been described in other forms of inherited parkinsonism: PARK6. Because mitophagy requires the interaction of parkin and PINK1, this explains the PARK2 and PARK6 forms of inherited parkinsonism as “nonefficient” removal of damaged mitochondria in postmitotic neurons. It remains, however, to be understood how this mechanism affecting the short-term turnover of mitochondria by mitophagy is compatible with the well known very slow disease progression, as documented by the mild phenotypic changes of mice expressing mutant PINK1 (67). An alternative molecular mechanism explaining the slowly progressive mitochondrial dysfunction in dopaminergic neurons is suggested to be related to clonal accumulation of deleted mtDNA molecules at the single cell level ((48, 49); see discussion in following section). This in turn would diminish the residual amount of wild-type mtDNA, thus leading to progressive mitochondrial dysfunction by reduced expression of mitochondrially encoded proteins, like certain subunits of respiratory chain. Elevated levels of mitochondria with nonfunctional respiratory chains could perhaps explain elevated levels of intrinsic ROS production (see above), affecting in turn mtDNA mutagenesis, as well as the progressive bioenergetic failure of neurons.

Genetic Mechanisms Explaining Disease Progression

  1. Top of page
  2. Abstract
  3. Introduction: Specific Properties of Neuronal Mitochondria
  4. Neurodegenerative Diseases with Evidence for Direct Mitochondrial Involvement
  5. Genetic Mechanisms Explaining Disease Progression
  6. Final Remarks
  7. Acknowledgements
  8. References

In opposite to other biomolecules of the cell, the main function of DNA does not alone depend on its biochemical properties, but is rather represented by the information stored in it. Damaged DNA molecules can undergo different repair processes, which might recover the original state of the DNA, but might also result in biochemically intact molecules with altered information content, that is, mutants (Fig. 2). This property of the DNA makes it a good candidate to be the molecular basis for long lasting and accumulating remnants of cell damage.

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Figure 2. Mechanisms of mutation accumulation in mitochondrial DNA. Failure in replication of mtDNA and environmental factors lead to mtDNA damage. Damaged molecules (indicated by star) are either eliminated or undergo repair processes. Repair might restore the original wild-type state, but it can also lead to biochemically intact molecules with altered or partially lost information content (mutant). Replicative segregation of mutated molecules contributes to the accumulation of mutations. BER, base excision repair; MMR, mismatch repair; DSBR, double strand break repair; POLG, mitochondrial DNA polymerase γ; ROS, reactive oxygen species being able to attack mtDNA.

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The most intensively investigated forms of mtDNA mutations are large deletions where a substantial part of the mitochondrial genome is missing. The exact mechanisms of mtDNA deletion formation are not known. Current hypotheses are based on properties of previously observed deleted mtDNA molecules. The fact that deletions have often been observed in the major arc between the two replication origins of the mitochondrial genome lead to the assumption that slipped-strand replication is one of the main sources of mtDNA deletion generation (68). Replication can, however, also play a role in deletion formation through inducing double-strand breaks (DSBs). Such damaged mtDNA molecules are generated at sites of stalled replication (69). If these linear DNA molecules (deletion precursors) are not eliminated by degradation, repair processes might convert them to intact but incomplete mtDNA molecules (70). The relevance of DSBs in deletion generation was demonstrated in a mouse model, where strand breaks were induced by expression of a mitochondrially targeted endonuclease (71). In this model system, many of the deletions had a breakpoint within the D-loop region of the mitochondrial genome, close to the replication-relevant termination associated sequence (72).

Beside replication stalling, another relevant source of DSBs is ROS. While nuclear DNA is located in a specialized cell organelle that is dedicated to the organization and protection of the chromosomes, mtDNA is forming nucleoids that are associated to the inner mitochondrial membrane, one of the energetically most active spots in the cell. Even normal electron flow through the complexes of the respiratory chain produces a certain amount of ROS, and it can further increase in cases of inhibited electron transport (see section “Mitochondrial Formation of ROS and Neurodegeneration,” (32)). Therefore, mitochondrial respiratory activity very likely plays a central role in mtDNA damage. The other way around, mtDNA codes for the key subunits of the respiratory chain, and its biosynthesis is probably regulated by the energetic needs of the cell. Failure in generating sufficient amounts of functional mtDNA molecules directly leads to respiratory deficiency. This reciprocal connection between mtDNA and mitochondrial respiration inspired the vicious circle hypothesis of progressive mitochondrial dysfunction (73). However, investigations of mtDNA alterations at the single cell level suggested that, beside mutagenesis, another process is equally relevant in the process of mutation accumulation: replicative segregation of mutated molecules. Single respiratory deficient neurons in substantia nigra of patients with PD display high amounts of single mtDNA deletion species, and different neurons are carrying different deletion species (48, 49). This suggests that the critical mass of mutated mtDNA molecules within a cell is reached not by repeated mutagenesis but mainly through the clonal expansion of a few mutated molecules. According to current hypotheses, this clonal expansion of deletions might be due to a replicative advantage of shorter mtDNA molecules (74). The time span that is required for this process to result in functionally significant amount of mutated mtDNA in a cell is estimated to be several decades (75). Interestingly, mitochondria containing high levels of mutated mtDNA do not always seem to be eliminated by the quality control pathway described in section “Mitochondrial Quality Control.” One possible reason for this might be the preservation of the membrane potential in mitochondria containing high levels of mutated mtDNA. Similar to ρ0 cells that completely lack mtDNA, the reverse action of adenine nucleotide translocase and proton translocating ATPase can keep in respiration incompetent mitochondria the mitochondrial membrane potential high by using the remaining ATP supply of the cell (produced by glycolysis). This would explain why high levels of pathogenic mtDNA mutations can easily accumulate in colon crypts (76) or in skeletal muscle fibers having a high glycolytic activity. In neurons, which cannot compensate easily the lacking ATP supply of oxidative phosphorylation by glycolysis, it appears more likely that mitochondria with high loads of pathogenic mutations approach a state of decreased membrane potential making them potential targets for quality control on the organelle level. Nevertheless, mitochondria containing high loads of mtDNA mutations tend also to accumulate in certain neurons (49), which might indicate some limitations in the operation of the mitochondrial quality control system.

The parallel action of mtDNA mutagenesis and replicative expansion of mitochondrial mutations is not specific for disease conditions, but it has also been described in normal aging. This raises the question as to what makes the difference between normal aging and progressive disease. One possibility is that insufficient mtDNA maintenance leads to increased rate of mutagenesis or, through decreased copy numbers, to increased speed of clonal expansion. This is the case in individuals with pathogenic mutations in proteins of mtDNA replication (POLG (77); POLG2 (78); Twinkle (79)), however, diseases caused by these mutations often manifest at much younger ages than common neurodegenerative diseases. Mutations in proteins that affect mitochondrial fusion (MFN2, OPA1) can cause a secondary disturbance of the mtDNA maintenance probably through the lack of appropriate content mixing. Accordingly, decreased mtDNA copy numbers (depletion) and multiple deletions have been observed in individuals with mutant MFN2 and OPA1 (80–82). Decreased copy numbers correlate with decreased respiratory enzyme activities, but it is not clear whether the respiratory deficiency plays the central role in the pathogenesis or rather the disturbed distribution of mitochondria within the neurons. Neurodegeneration associated with accumulation of clonal mtDNA deletions was also described in temporal lobe epilepsy with hippocampus sclerosis (54, 83). It is hypothesized that oxidative damage of mtDNA due to febrile seizures in childhood could be the reason for increased mutagenesis. A slow clonal expansion of these deletions would then lead to respiratory dysfunctions in hippocampal pyramidal neurons and interneurons causing cell death and intractable chronic epilepsy at adult age (54, 84). Clonal expansions of mtDNA deletions have also been observed in patients with multiple sclerosis (MS) and are suggested to be an important contributor to neurodegeneration in MS (85, 86). Here, chronic inflammation appears to trigger mtDNA mutagenesis and initiate clonal expansion.

Figure 3 provides an overview of genetical and physiological factors whose proposed interplay culminates in accumulation of mutated mtDNA, respiratory failure, and insufficient ATP supply, affecting neurotransmitter release and leading finally to neuronal degeneration.

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Figure 3. Hypothetical mechanism of mitochondrial involvement in neurodegeneration. The numbers indicate different groups of genes being mutated in inherited forms of neurodegenerative diseases. 1 (maternally transmitted mtDNA mutations): LHON (MT-ND1, MT-ND4, MT-ND6); progressive myoclonic epilepsy (MT-TK, MT-TF, MT-TL1); Leigh syndrome (MT-ATP6); 2 (mutations in genes affecting mtDNA maintenance): MIRAS and progressive myoclonic epilepsy (POLG); IOSCA (c10orf2); 3 (mutations in genes affecting mitochondrial fusion and fission): CMT2A2 (MFN2); OPA1 (OPA1); OPA3 (OPA3); 4 (mutations in genes affection mitochondrial quality control): PARK2 (PARKIN); PARK6 (PINK1); PARK7 (PARK7); SPG7 (SPG7); SCA28 (AFG3L2).

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Final Remarks

  1. Top of page
  2. Abstract
  3. Introduction: Specific Properties of Neuronal Mitochondria
  4. Neurodegenerative Diseases with Evidence for Direct Mitochondrial Involvement
  5. Genetic Mechanisms Explaining Disease Progression
  6. Final Remarks
  7. Acknowledgements
  8. References

The fact that many of the mitochondrial proteins whose mutations have been found to be associated with inherited neurodegenerative disorders do not directly affect oxidative phosphorylation could be interpreted that insufficient neuronal ATP production plays only a subordinate role in neurodegeneration. In opposite, we hypothesize that, in case of neurons, local imbalances between ATP demand and supply might play a central role in the pathogenesis. The effects of altered mitochondrial dynamics and insufficient quality control are especially dramatic in subcellular compartments that have a high energy demand and that are located far away from the soma, such as the presynaptic terminal. Local, rather mild ATP shortages would explain why neurodegenerative disorders have a much later age of onset than typical mitochondrial syndromes with primary failure of the oxidative phosphorylation. On the other hand, the progressive nature of neurodegenerative disorders might also depend on the general decline of ATP production in single neurons caused by accumulating somatic mtDNA mutations, a process that is also observed during normal aging. The concerted action of local ATP insufficiency and the time-dependent clonal expansion of somatic mtDNA mutations would explain the specific susceptibility of neurons in neurodegenerative disorders.


  1. Top of page
  2. Abstract
  3. Introduction: Specific Properties of Neuronal Mitochondria
  4. Neurodegenerative Diseases with Evidence for Direct Mitochondrial Involvement
  5. Genetic Mechanisms Explaining Disease Progression
  6. Final Remarks
  7. Acknowledgements
  8. References

This work was supported by the Bundesministerium für Bildung und Forschung (mitoNET 01GM0868), the Deutsche Forschungsgemeinschaft (SFB TR3 A11 and D12), and the Stiftung für Medizinische Wissenschaft, Frankfurt am Main.


  1. Top of page
  2. Abstract
  3. Introduction: Specific Properties of Neuronal Mitochondria
  4. Neurodegenerative Diseases with Evidence for Direct Mitochondrial Involvement
  5. Genetic Mechanisms Explaining Disease Progression
  6. Final Remarks
  7. Acknowledgements
  8. References
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