TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated degradation in damaged mitochondria

被引：22

作者：

Akabane, Shiori ^{[1
,2
]}

Watanabe, Kiyona ^{[1
]}

Kosako, Hidetaka ^{[3
]}

Yamashita, Shun-ichi ^{[4
]}

Nishino, Kohei ^{[3
]}

Kato, Masahiro ^{[1
]}

Sekine, Shiori ^{[5
]}

Kanki, Tomotake ^{[4
]}

Matsuda, Noriyuki ^{[6
]}

Endo, Toshiya ^{[2
,7
]}

Oka, Toshihiko ^{[1
]}

机构：

[1] Rikkyo Univ, Dept Life Sci, Tokyo 1718501, Japan

[2] Kyoto Sangyo Univ, Fac Life Sci, Kyoto 6038555, Japan

[3] Tokushima Univ, Fujii Mem Inst Med Sci, Div Cell Signaling, Tokushima 7708503, Japan

[4] Niigata Univ, Dept Cellular Physiol, Grad Sch Med & Dent Sci, Niigata 9518510, Japan

[5] Univ Pittsburgh, Aging Inst, Dept Med, Div Cardiol, Pittsburgh, PA 15219 USA

[6] Tokyo Med & Dent Univ, Med Res Inst, Biomol Pathogenesis, Tokyo 1138519, Japan

[7] Kyoto Sangyo Univ, Inst Prot Dynam, Kyoto 6038555, Japan

来源：

CELL REPORTS | 2023年 / 42卷 / 05期

基金：

日本学术振兴会;

关键词：

PROTEIN IMPORT; INNER MEMBRANE; PARKIN; COMPLEX; RECRUITMENT; UBIQUITIN; IDENTIFICATION; RECEPTORS; STABILITY; TIM50;

D O I：

10.1016/j.celrep.2023.112454

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

PINK1 is activated by autophosphorylation and forms a high-molecular-weight complex, thereby initiating the selective removal of damaged mitochondria by autophagy. Other than translocase of the outer mitochon-drial membrane complexes, members of PINK1-containing protein complexes remain obscure. By mass spectrometric analysis of PINK1 co-immunoprecipitates, we identify the inner membrane protein TIM23 as a component of the PINK1 complex. TIM23 downregulation decreases PINK1 levels and significantly delays autophosphorylation, indicating that TIM23 promotes PINK1 accumulation in response to depolarization. Moreover, inactivation of the mitochondrial protease OMA1 not only enhances PINK1 accumulation but also represses the reduction in PINK1 levels induced by TIM23 downregulation, suggesting that TIM23 facil-itates PINK1 activation by safeguarding against degradation by OMA1. Indeed, deficiencies of pathogenic PINK1 mutants that fail to interact with TIM23 are partially restored by OMA1 inactivation. These findings indi-cate that TIM23 plays a distinct role in activating mitochondrial autophagy by protecting PINK1.

引用

页数：19

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