Mitochondrial translation deficiency impairs NAD + ‐mediated lysosomal acidification
Open Access
- 2 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 40 (8), e105268
- https://doi.org/10.15252/embj.2020105268
Abstract
Mitochondrial translation dysfunction is associated with neurodegenerative and cardiovascular diseases. Cells eliminate defective mitochondria by the lysosomal machinery via autophagy. The relationship between mitochondrial translation and lysosomal function is unknown. In this study, mitochondrial translation‐deficient hearts from p32‐knockout mice were found to exhibit enlarged lysosomes containing lipofuscin, suggesting impaired lysosome and autolysosome function. These mice also displayed autophagic abnormalities, such as p62 accumulation and LC3 localization around broken mitochondria. The expression of genes encoding for nicotinamide adenine dinucleotide (NAD+) biosynthetic enzymes—Nmnat3 and Nampt—and NAD+ levels were decreased, suggesting that NAD+ is essential for maintaining lysosomal acidification. Conversely, nicotinamide mononucleotide (NMN) administration or Nmnat3 overexpression rescued lysosomal acidification. Nmnat3 gene expression is suppressed by HIF1α, a transcription factor that is stabilized by mitochondrial translation dysfunction, suggesting that HIF1α‐Nmnat3‐mediated NAD+ production is important for lysosomal function. The glycolytic enzymes GAPDH and PGK1 were found associated with lysosomal vesicles, and NAD+ was required for ATP production around lysosomal vesicles. Thus, we conclude that NAD+ content affected by mitochondrial dysfunction is essential for lysosomal maintenance.Keywords
Funding Information
- Japan Society for the Promotion of Science (17H01550, 15H04764, 18K15421, 25253041)
This publication has 57 references indexed in Scilit:
- NAD metabolism: Implications in aging and longevityAgeing Research Reviews, 2018
- Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome AcidificationCell Reports, 2015
- Disturbed mitochondrial dynamics and neurodegenerative disordersNature Reviews Neurology, 2014
- Nicotinamide Mononucleotide, an Intermediate of NAD+ Synthesis, Protects the Heart from Ischemia and ReperfusionPLOS ONE, 2014
- Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvationProceedings of the National Academy of Sciences of the United States of America, 2011
- Mitochondrial Energetics and TherapeuticsAnnual review of pathology, 2010
- The role of autophagy during the early neonatal starvation periodNature, 2004
- Oxidative damage and mitochondrial decay in aging.Proceedings of the National Academy of Sciences of the United States of America, 1994
- Transfer of 1,3-diphosphoglycerate between glyceraldehyde 3-phosphate dehydrogenase and 3-phosphoglycerate kinase via an enzyme-substrate-enzyme complexBiochemistry, 1982
- Identification and characterization of a proton pump on lysosomes by fluorescein-isothiocyanate-dextran fluorescence.Proceedings of the National Academy of Sciences of the United States of America, 1982