Proteasome Impairment Induces Recovery of Mitochondrial Membrane Potential and an Alternative Pathway of Mitochondrial Fusion

Abstract

Mitochondria are vital and highly dynamic organelles that continuously fuse and divide to maintain mitochondrial quality. Mitochondrial dysfunction impairs cellular integrity and is known to be associated with various human diseases. However, the mechanism by which the quality of mitochondria is maintained remains largely unexplored. Here we show that impaired proteasome function recovers the growth of yeast cells lacking Fzo1, a pivotal protein for mitochondrial fusion. Decreased proteasome activity increased the mitochondrial oxidoreductase protein Mia40 and the ratio of the short isoform of mitochondrial intermembrane protein Mgm1 (s-Mgm1) to the long isoform (l-Mgm1). The increase in Mia40 restored mitochondrial membrane potential, while the increase in the s-Mgm1/l-Mgm1 ratio promoted mitochondrial fusion in an Fzo1-independent manner. Our findings demonstrate a new pathway for mitochondrial quality control that is induced by proteasome impairment. Mitochondria are highly dynamic organelles that continuously divide and fuse with each other (1, 2). Mitochondrial fusion and fission contribute to quality control of mitochondria. Under moderate-stress conditions, mitochondrial fusion is stimulated to cure damaged mitochondria by fusing to healthy mitochondria. On the other hand, severely damaged mitochondria are eliminated by mitophagy, where uneven distribution of damaged proteins and asymmetrical mitochondrial fission contribute to selective degradation of damaged mitochondria by autophagy (3). Loss of mitochondrial fusion leads to fragmented mitochondria caused by ongoing fission, mitochondrial DNA loss, and decrease in ATP production, manifested by poor growth in yeast or embryonic lethality in mammals.Previous reports showed that at least two dynamin-related proteins (DRPs), Fzo1/mitofusin and Mgm1/OPA1, are required for mitochondrial fusion, and one DRP, Dnm1/Drp1, regulates mitochondrial fission in yeast/mammals. Mitochondrial outer membrane protein Ugo1 bridges interactions between Fzo1 and Mgm1 (4-8). Although detailed fusion mechanisms remain to be solved, the ubiquitin-proteasome system has been suggested to regulate mitochondrial dynamics. Mutations in Rpn11, which cleaves polyubiquitin chains from substrate proteins, and Blm10, a homolog of proteasome activator PA200, induced mitochondrial fragmentation in a Dnm1-dependent manner (9-11), suggesting that the proteasome plays an important role in mitochondrial fusion-fission balance. In addition, the proteasome positively and negatively regulates mitochondrial fusion: degradation of Fzo1 either downregulates mitochondrial fusion or accomplishes fusion events after transoligomerization of Fzo1, depending on context, in yeast (12)(13)(14).The 26S proteasome is a 2.5-MDa protease complex conserved among eukaryotes. It is made up of 66 subunits and can be divided into two complexes: a catalytic 20S core particle (CP), and a 19S regulatory particle (RP). The proteasome selectively degrades proteins tagged with ubiquitin chains. This selective degradation ...

The intermembrane space protein Mix23 is a novel stress-induced mitochondrial import factor

“…The molecular function of Mix23 in the IMS and the reasons that this factor is up-regulated during mitoprotein-induced stress remain unclear. An Rpn4-dependent regulation was also described before for Mia40 (33,66,67). Still, we found no indication that Mix23 is of relevance for the functionality of the mitochondrial disulfide relay in the IMS, and the deletion of MIX23 did not lead to synthetic defects in mia40-3 mutants.…”

Autophagy in Rat Müller Glial Cells Is Modulated by the Sirtuin 4/AMPK/mTOR Pathway and Induces Apoptosis under Oxidative Stress

“…The mitochondrial membrane potential (ΔΨm) is an independent indicator of mitochondrial quality, responsible for basic functions of the mitochondria, such as protein import and synthesis in addition to ATP generation [ 27 , 28 ]. The sustained depolarization of mitochondria can induce apoptosis in target cells [ 29 ].…”

Effects of a proteasome inhibitor on the riboflavin production in Ashbya gossypii

“…It was reported that mitochondrial function regulates 26S proteasome assembly and UPS regulates mitochondrial homeostasis (Alsayyah et al, 2020; Meul et al, 2020). Mitochondrial proteins in the outer and inner membranes and matrix are degraded by UPS following its ubiquitination, and UPS controls mitochondrial functions (Lavie et al, 2018; Lehmann et al, 2016; Liao et al, 2020; Shirozu et al, 2015). In addition, 3‐nitropropionic acid, which is known as an SDH inhibitor, influences the proteasome activity in Huntington's disease model cells (Hunter et al, 2007).…”