Yagi Mikako, Toshima Takahiro, Amamoto Rie, Do Yura, Hirai Haruka, Setoyama Daiki, Kang Dongchon, Uchiumi Takeshi
Department of Clinical Chemistry and Laboratory Medicine, Kyushu University, Fukuoka, Japan.
Department of Health Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
EMBO J. 2021 Apr 15;40(8):e105268. doi: 10.15252/embj.2020105268. Epub 2021 Feb 2.
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.
线粒体翻译功能障碍与神经退行性疾病和心血管疾病相关。细胞通过自噬利用溶酶体机制清除有缺陷的线粒体。线粒体翻译与溶酶体功能之间的关系尚不清楚。在本研究中，发现p32基因敲除小鼠的线粒体翻译缺陷型心脏表现出含有脂褐素的溶酶体增大，提示溶酶体和自噬溶酶体功能受损。这些小鼠还表现出自噬异常，如p62积累和LC3在线粒体破裂周围的定位。编码烟酰胺腺嘌呤二核苷酸（NAD）生物合成酶——Nmnat3和Nampt——的基因表达及NAD水平降低，提示NAD对维持溶酶体酸化至关重要。相反，烟酰胺单核苷酸（NMN）给药或Nmnat3过表达可挽救溶酶体酸化。Nmnat3基因表达受HIF1α抑制，HIF1α是一种由线粒体翻译功能障碍稳定的转录因子，提示HIF1α-Nmnat3介导的NAD产生对溶酶体功能很重要。发现糖酵解酶GAPDH和PGK1与溶酶体囊泡相关，且溶酶体囊泡周围的ATP产生需要NAD。因此，我们得出结论，受线粒体功能障碍影响的NAD含量对溶酶体维持至关重要。
