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[2021/02/05]
Mitochondrial translation deficiency impairs NAD-mediated lysosomal acidification(Takeshi Uchiumi)
In a new study published in the EMBO Journal, researchers consisting of Assistant Professor Mikako Yagi (first author), Professor Takeshi Uchiumi (corresponding author) report that crosstalk between mitochondria and lysosomal function for mitophagy has been revealed. HIF1α-Nmnat3-mediated NAD+ production which affected by mitochondrial translation dysfunction is essential for lysosomal maintenance.
 
Mitochondrial translation dysfunction is associated with neurodegenerative and cardiovascular diseases. Cells eliminate defective mitochondria by lysosomal machinery via autophagy. However, the relationship between mitochondrial translation and lysosomal function is unknown. 
 
We first created organ-specific knockout mice of the mitochondrial translational regulator p32 protein. Thus, we have succeeded in elucidating a new molecular mechanism involved in autophagy by reducing lysosomal acidification due to mitochondrial disorders. 
 
In this study, we found that
1.   Mitochondrial translation-deficient hearts showed increased HIF1α expression 
2.  HIF1α suppressed Nmnat3 gene expression leading to reduced NAD+ contents 
3.  Glycolytic enzyme such as GAPDH and PGK1 were associated with lysosomal vesicles for localized ATP production 
4.  NMN administration or Nmnat3 overexpression rescued lysosomal acidification, suggesting that NAD+ is essential for lysosomal acidification
 
It has been found that this reduction of lysosomal function, which in turn causes a decrease in autophagy and is involved in the pathological condition. Since NAD is essential for lysosomal function, increasing the amount of intracellular NAD is expected to be a treatment for mitochondrial-mediated aging-related diseases.
 
Mitochondrial translation deficiency impairs NAD-mediated lysosomal acidification
Mikako Yagi, Takahiro Toshima, Rie Amamoto, Yura Do, Haruka Hirai, Daiki Setoyama, Dongchon Kang and Takeshi Uchiumi
EMBO Journal,10.15252/embj.2020106663

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