Mitochondrial Translation Deficiency Impairs NAD -mediated Lysosomal Acidification

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2021 Feb 2

PMID 33528041

Citations 24

Authors

Mikako Yagi

Takahiro Toshima

Rie Amamoto

Yura Do

Haruka Hirai

Daiki Setoyama

Dongchon Kang

Takeshi Uchiumi

Affiliations

Soon will be listed here.

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.

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