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1.
Nat Commun ; 9(1): 4859, 2018 11 19.
Article in English | MEDLINE | ID: mdl-30451844

ABSTRACT

While young muscle is capable of restoring the original architecture of damaged myofibers, aged muscle displays a markedly reduced regeneration. We show that expression of the "anti-aging" protein, α-Klotho, is up-regulated within young injured muscle as a result of transient Klotho promoter demethylation. However, epigenetic control of the Klotho promoter is lost with aging. Genetic inhibition of α-Klotho in vivo disrupted muscle progenitor cell (MPC) lineage progression and impaired myofiber regeneration, revealing a critical role for α-Klotho in the regenerative cascade. Genetic silencing of Klotho in young MPCs drove mitochondrial DNA (mtDNA) damage and decreased cellular bioenergetics. Conversely, supplementation with α-Klotho restored mtDNA integrity and bioenergetics of aged MPCs to youthful levels in vitro and enhanced functional regeneration of aged muscle in vivo in a temporally-dependent manner. These studies identify a role for α-Klotho in the regulation of MPC mitochondrial function and implicate α-Klotho declines as a driver of impaired muscle regeneration with age.


Subject(s)
Aging/genetics , DNA, Mitochondrial/genetics , Mitochondria/genetics , Muscle, Skeletal/metabolism , Myoblasts/metabolism , Receptors, Cell Surface/genetics , Stem Cells/metabolism , Aging/metabolism , Aging/pathology , Animals , DNA Methylation , DNA, Mitochondrial/metabolism , Epigenesis, Genetic , Gene Expression Regulation, Developmental , Glucuronidase , Klotho Proteins , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondria/metabolism , Muscle, Skeletal/pathology , Myoblasts/pathology , Promoter Regions, Genetic , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptors, Cell Surface/antagonists & inhibitors , Receptors, Cell Surface/metabolism , Regeneration/genetics , Signal Transduction , Stem Cells/pathology
2.
Cell Death Differ ; 23(7): 1140-51, 2016 07.
Article in English | MEDLINE | ID: mdl-26742431

ABSTRACT

Mitophagy is critical for cell homeostasis. Externalization of the inner mitochondrial membrane phospholipid, cardiolipin (CL), to the surface of the outer mitochondrial membrane (OMM) was identified as a mitophageal signal recognized by the microtubule-associated protein 1 light chain 3. However, the CL-translocating machinery remains unknown. Here we demonstrate that a hexameric intermembrane space protein, NDPK-D (or NM23-H4), binds CL and facilitates its redistribution to the OMM. We found that mitophagy induced by a protonophoric uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), caused externalization of CL to the surface of mitochondria in murine lung epithelial MLE-12 cells and human cervical adenocarcinoma HeLa cells. RNAi knockdown of endogenous NDPK-D decreased CCCP-induced CL externalization and mitochondrial degradation. A R90D NDPK-D mutant that does not bind CL was inactive in promoting mitophagy. Similarly, rotenone and 6-hydroxydopamine triggered mitophagy in SH-SY5Y cells was also suppressed by knocking down of NDPK-D. In situ proximity ligation assay (PLA) showed that mitophagy-inducing CL-transfer activity of NDPK-D is closely associated with the dynamin-like GTPase OPA1, implicating fission-fusion dynamics in mitophagy regulation.


Subject(s)
Cardiolipins/metabolism , Mitochondria/metabolism , Mitochondrial Membranes/metabolism , Mitophagy , Nucleoside Diphosphate Kinase D/metabolism , Animals , Autophagy/drug effects , Carbonyl Cyanide m-Chlorophenyl Hydrazone/toxicity , Cardiolipins/analysis , Cell Line , GTP Phosphohydrolases/metabolism , HeLa Cells , Humans , Lysosomes/metabolism , Lysosomes/pathology , Mice , Microtubule-Associated Proteins/metabolism , Mitochondria/pathology , Mitophagy/drug effects , Mutagenesis, Site-Directed , Nucleoside Diphosphate Kinase D/antagonists & inhibitors , Nucleoside Diphosphate Kinase D/genetics , Oxidopamine/pharmacology , Protein Binding , RNA Interference , Rotenone/pharmacology
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