Solid-phase inclusion as a mechanism for regulating unfolded proteins in the mitochondrial matrix

Linhao Ruan; Joshua T McNamara; Xi Zhang; Alexander Chih-Chieh Chang; Jin Zhu; Yi Dong; Gordon Sun; Amy Peterson; Chan Hyun Na; Rong Li

doi:10.1126/sciadv.abc7288

Solid-phase inclusion as a mechanism for regulating unfolded proteins in the mitochondrial matrix

Sci Adv. 2020 Aug 5;6(32):eabc7288. doi: 10.1126/sciadv.abc7288. eCollection 2020 Aug.

Authors

Linhao Ruan^{1

2}, Joshua T McNamara^{1

2}, Xi Zhang¹, Alexander Chih-Chieh Chang^{1

3}, Jin Zhu¹, Yi Dong^{1

4}, Gordon Sun^{1

5}, Amy Peterson², Chan Hyun Na⁶, Rong Li^{1

3

7}

Affiliations

¹ Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Biochemistry, Cellular and Molecular Biology (BCMB) Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
³ Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
⁴ Immunology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁵ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
⁶ Department of Neurology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ Mechanobiology Institute and Department of Biological Science, National University of Singapore, Singapore 117411, Singapore.

Abstract

Proteostasis declines with age, characterized by the accumulation of unfolded or damaged proteins. Recent studies suggest that proteins constituting pathological inclusions in neurodegenerative diseases also enter and accumulate in mitochondria. How unfolded proteins are managed within mitochondria remains unclear. Here, we found that excessive unfolded proteins in the mitochondrial matrix of yeast cells are consolidated into solid-phase inclusions, which we term deposits of unfolded mitochondrial proteins (DUMP). Formation of DUMP occurs in mitochondria near endoplasmic reticulum-mitochondria contact sites and is regulated by mitochondrial proteins controlling the production of cytidine 5'-diphosphate-diacylglycerol. DUMP formation is age dependent but accelerated by exogenous unfolded proteins. Many enzymes of the tricarboxylic acid cycle were enriched in DUMP. During yeast cell division, DUMP formation is necessary for asymmetric inheritance of damaged mitochondrial proteins between mother and daughter cells. We provide evidence that DUMP-like structures may be induced by excessive unfolded proteins in human cells.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Abstract

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