Endolysosomal two-pore channels regulate autophagy in cardiomyocytes
Vanessa García-Rúa, Sandra Feijóo-Bandín, Diego Rodríguez-Penas, Ana Mosquera-Leal, Emad Abu-Assi, Andrés Beiras, Luisa María Seoane, Pamela Lear, John Parrington, Manuel Portolés, Esther Roselló-Lletí, Miguel Rivera, Oreste Gualillo, Valentina Parra, Joseph A. Hill, Beverly Rothermel, José Ramón González-Juanatey and Francisca Lago
Article first published online: 4 FEB 2016 | DOI: 10.1113/JP271332
- Two-pore channels (TPCs) were identified as a novel family of endolysosome-targeted calcium release channels gated by nicotinic acid adenine dinucleotide phosphate, as also as intracellular Na+ channels able to control endolysosomal fusion, a key process in autophagic flux.
- Autophagy, an evolutionarily ancient response to cellular stress, has been implicated in the pathogenesis of a wide range of cardiovascular pathologies, including heart failure.
- We report direct evidence indicating that TPCs are involved in regulating autophagy in cardiomyocytes, and that TPC knockout mice show alterations in the cardiac lysosomal system. TPC downregulation implies a decrease in the viability of cardiomyocytes under starvation conditions. In cardiac tissues from both humans and rats, TPC transcripts and protein levels were higher in females than in males, and correlated negatively with markers of autophagy.
- We conclude that the endolysosomal channels TPC1 and TPC2 are essential for appropriate basal and induced autophagic flux in cardiomyocytes, and also that they are differentially expressed in male and female hearts.