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Mitochondrial translation deficiency impairs NAD + ‐mediated lysosomal acidification
Author(s) -
Yagi Mikako,
Toshima Takahiro,
Amamoto Rie,
Do Yura,
Hirai Haruka,
Setoyama Daiki,
Kang Dongchon,
Uchiumi Takeshi
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020105268
Subject(s) - nad+ kinase , nicotinamide mononucleotide , biology , mitochondrion , nicotinamide adenine dinucleotide , lysosome , autophagy , biochemistry , glyceraldehyde 3 phosphate dehydrogenase , nicotinamide phosphoribosyltransferase , microbiology and biotechnology , mannose 6 phosphate receptor , enzyme , dehydrogenase , apoptosis
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.