Mitochondrial Proteolysis and Metabolic Control

Abstract

Mitochondria are metabolic hubs that use multiple proteases to maintain proteostasis and to preserve their overall quality. A decline of mitochondrial proteolysis promotes cellular stress and may contribute to the aging process. Mitochondrial proteases have also emerged as tightly regulated enzymes required to support the remarkable mitochondrial plasticity necessary for metabolic adaptation in a number of physiological scenarios. Indeed, the mutation and dysfunction of several mitochondrial proteases can cause specific human diseases with severe metabolic phenotypes. Here, we present an overview of the proteolytic regulation of key mitochondrial functions such as respiration, lipid biosynthesis, and mitochondrial dynamics, all of which are required for metabolic control. We also pay attention to how mitochondrial proteases are acutely regulated in response to cellular stressors or changes in growth conditions, a greater understanding of which may one day uncover their therapeutic potential.

Figure 1.

Proteases controlling mitochondrial gene expression and oxidative phosphorylation (OXPHOS) assembly. (A) Peptidase Lon (LONP) regulates mitochondrial genome maintenance and transcription by binding to mitochondrial DNA (mtDNA) and degrading mitochondrial replicative helicase Twinkle and transcription factor A (TFAM). (B) Several proteases control mitochondrial protein synthesis. LONP degrades ribosomal subunit MRPL32 and CLPXP 12S ribosomal RNA (rRNA) chaperone ERAL1 and messenger RNA (mRNA) polyadenylation enzyme leucine-rich pentatricopeptide repeat domain-containing protein 1 (LRPPRC1). Matrix AAA⁺ (m-AAA⁺) protease cleaves newly synthesized mitochondrial translation products and MRLP32. (C) OMA1, ATP23, m-AAA, YME1L, LONP, and CLPXP are all participating in the degradation of OXPHOS subunits.

Figure 2.

Proteolytic control of mitochondrial dynamics. Mitochondrial fusion (upper) and fission (lower) depend on the regulation of mitochondrial dynamics factors by proteolysis. MFN1 and MFN2 promote outer mitochondrial membrane (OMM) fusion and they are negatively regulated by the deubiquitinase USP30. YME1L and OMA1 process OPA1 to regulate inner mitochondrial membrane (IMM) fusion. Excessive processing of membrane-bound long-form (L)-OPA1 by OMA1 limits fusion and promotes mitochondrial division.

Figure 3.

Mitochondrial proteases and lipid metabolism. PARL processes lipid transfer protein STARD7 and regulates its localization between mitochondria and cytoplasm. STARD1 transports cholesterol (C) to the outer mitochondrial membrane (OMM) but can be degraded by LONP in the matrix. The PRELID1–TRIAP complex and PRELID3B–TRIAP complex transport phosphatidic acid (PA) and phosphatidyl serine (PS), respectively, across the intermembrane space (IMS) and are degraded by YME1L. Phosphatidylserine carboxylase (PSD1) is cleaved by LACTB and PSD1 is also processing itself and thus switching from protease into a decarboxylase.

Figure 4.

Proteolytic regulation of PINK1/Parkin mitophagy. In a healthy mitochondrion with a normal membrane potential (ΔΨmt), PARL processes newly imported PINK1 at the inner mitochondrial membrane (IMM), which subsequently leaves the mitochondrion and is degraded by the proteasome. Mitochondrial dysfunction blocks PINK1 import and promotes PINK1 accumulation in the outer mitochondrial membrane (OMM). Here, PINK1 selectively recruits the E3-ligase Parkin, which ubiquitylates mitophagy receptor (R) proteins; an action suppressed in healthy mitochondria by USP30 deubiquitylase activity. These ubiquitin signals are recognized by mitophagy adaptor (A) proteins that interact with the autophagosomal protein LC3, resulting in the engulfment of the mitochondrion and delivery to the lysosome.