
TIMM50 欠乏は、酸化的リン酸化系とミトコンドリアリボソームの機能低下を引き起こし、神経細胞の ATP 産生能力と神経活動を低下させる。


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TIMM50, an essential TIM23 complex subunit, is suggested to facilitate the import of ∼60% of the mitochondrial proteome. In this study, we characterized a TIMM50 disease causing mutation in human fibroblasts, and noted significant decreases in TIM23 core protein levels (TIMM50, TIMM17A/B, and TIMM23). Strikingly, TIMM50 deficiency had no impact on the steady state levels of most of its substrates, challenging the currently accepted import dogma of the essential general import role of TIM23 and suggesting that fully functioning TIM23 complex is not essential for maintaining the steady state level of the majority of mitochondrial proteins. As TIMM50 mutations have been linked to severe neurological phenotypes, we aimed to characterize TIMM50 defects in manipulated mammalian neurons. TIMM50 knockdown in mouse neurons had a minor effect on the steady state level of most of the mitochondrial proteome, supporting the results observed in patient fibroblasts. Amongst the few affected TIM23 substrates, a decrease in the steady state level of components of the intricate oxidative phosphorylation and mitochondrial ribosome complexes was evident. This led to declined respiration rates in fibroblasts and neurons, reduced cellular ATP levels and defective mitochondrial trafficking in neuronal processes, possibly contributing to the developmental defects observed in patients with TIMM50 disease. Finally, increased electrical activity was observed in TIMM50 deficient mice neuronal cells, which correlated with reduced levels of KCNJ10 and KCNA2 plasma membrane potassium channels, likely underlying the patients’ epileptic phenotype.

### Competing Interest Statement

The authors have declared no competing interest.

Biochemical and neurophysiological effects of deficiency of the mitochondrial import protein TIMM50

ミトコンドリア輸送タンパク質-timm50-の欠乏が引き起こす生化学的および神経生理学的影響


ミトコンドリア輸送タンパク質 TIMM50 の欠乏が引き起こす生化学的および神経生理学的影響
