CHCHD2 and CHCHD10 regulate mitochondrial dynamics and integrated stress response

Yu Ruan,Yaping Che,Zhenhuan Luo,Jin Cheng,Jiaqiao Hu,Qi Han,He He,Yanyan Liu,Qinghua Zhou

doi:10.1038/s41419-022-04602-5

Abstract

Mitochondrial dysfunction is becoming one of the main pathology factors involved in the etiology of neurological disorders. Recently, mutations of the coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and 10 (CHCHD10) which encode two homologous proteins that belong to the mitochondrial CHCH domain protein family, are linked to Parkinson’s disease and amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), respectively. However, the physiological and pathological roles of these twin proteins have not been well elaborated. Here, we show that, in physiological conditions, CHCHD2 and CHCHD10 interact with OMA1 and suppress its enzyme activity, which not only restrains the initiation of the mitochondrial integrated response stress (mtISR), but also suppresses the processing of OPA1 for mitochondrial fusion. Further, during mitochondria stress-induced by carbonyl cyanide m-chlorophenylhydrazone (CCCP) treatment, CHCHD2 and CHCHD10 translocate to the cytosol and interacte with eIF2a, which attenuates mtISR overactivation by suppressing eIF2a phosphorylation and its downstream response. As such, knockdown of CHCHD2 and CHCHD10 triggers mitochondrial ISR, and such cellular response is enhanced by CCCP treatment. Therefore, our findings demonstrate the first “mtISR suppressor” localized in mitochondria for regulating stress responses in mammalian cells, which has a profound pathological impact on the CHCH2/CHCH10-linked neurodegenerative disorder.

Highlights

Mitochondria are double membrane-bound subcellular organelles well-known for producing ATP and controlling metabolism
CHCHD2 and CHCHD10 are homologous mitochondrial proteins and their mutations are identified with neurodegenerative disease [23]
We report that CHCHD2 single knockdown as well as CHCHD2 and CHCHD10 double knockdown can slow down mitochondrial fusion and fission (Fig. 1D)

Summary

INTRODUCTION

Mitochondria are double membrane-bound subcellular organelles well-known for producing ATP and controlling metabolism. Mitochondrial dynamics-related proteins, including Mfn, Mfn and Mff had very similar expression levels between control cells CHCHD2 and CHCHD10 interact with OMA1 to inhibit its and CHCHD2/CHCHD10 knockdown cells (Fig. 1A) These protease activity results demonstrated that despite no effect on mitochondrial As we knew, upon mitochondrial stress, DELE1 is cleaved by OMA1 morphology, loss of CHCHD2/CHCHD10 slowed down the rate of in mitochondria and enters into the cytosol to interact with and mitochondrial fusion and fission. Western Blot analysis showed that the degradation rate of CHCH2 mutants, T61I and R145Q, was significantly slower than that of the wild-type CHCHD2 (Fig. 6B, C), indicating that neurodegenerative disease-related CHCHD2 mutants are resistant to degradation by Yme1L and OMA1 under mitochondrial stress

DISCUSSION

Findings

MATERIALS AND METHODS