Mitochondrial Proteolysis and Metabolic Control

Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Mitochondrial Proteolysis and Metabolic Control Sofia Ahola, Thomas Langer, and Thomas MacVicar Department of Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany Correspondence: [email protected] 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 nec- essary 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 dy- namics, 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. ore than a billion years of evolution inner mitochondrial membrane (IMM), which Msince their fateful endosymbiotic origin is separated from the cytosol by the intermem- have directed mitochondria to play central brane space (IMS) and outer mitochondrial roles in metabolism and other cellular functions. membrane (OMM). Proteostasis in each sub- For instance, precise regulation of mitochondri- compartment is maintained by a number of al function is required for the production of mitochondrial proteases (mitoproteases) that ATP by oxidative phosphorylation (OXPHOS), promote protein quality control by degrading the maintenance of calcium homeostasis, and misfolded proteins and by processing newly im- programmed cell death. Only 13 mitochondrial ported proteins to facilitate their biogenesis proteins (∼1% of the total mitochondrial prote- (Quiros et al. 2015). Mitochondrial proteolysis ome) are encoded by resident mitochondrial is therefore a frontline mitochondrial quality- DNA (mtDNA) with the remainder originating control mechanism that combines with others, from the nucleus. These proteins are synthe- including reactive oxygen species (ROS) scav- sized on cytosolic ribosomes and directed to enging and mitophagy, to maintain overall mi- four distinct submitochondrial compartments tochondrial fitness. that are defined by the organelle’s unique double Acting as quality-control enzymes, all mito- membrane-bound structure. The mitochondrial proteases are likely to impact metabolism be- matrix is surrounded by the cristae-forming cause mitochondria represent a core metabolic Editors: Richard I. Morimoto, F. Ulrich Hartl, and Jeffery W. Kelly Additional Perspectives on Protein Homeostasis available at www.cshperspectives.org Copyright © 2019 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a033936 1 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press S. Ahola et al. hub. Nevertheless, recent advancements have prised of the peptidase PMCB and its noncata- demanded that we look beyond this classical lytic homolog PMCA (Mossmann et al. 2012). A description of mitoproteases. It is now clear matrix soluble complex, MPP processes the pos- that mitochondrial proteolysis offers a valuable itively charged presequence of the vast majority node for the regulation of specific mitochondrial of newly imported proteins destined for the functions and can be modulated by an array of matrix, IMM or IMS. Discarded presequence signaling inputs. Consequently, dysfunctional peptides are targeted by proteases within mito- mitoproteases contribute to a plethora of hu- chondria, such as Cym1 and Ste23 in yeast or man diseases, including cancer and neurode- PreP in humans, to be rapidly degraded and to generation and are strongly associated with the prevent their potentially toxic accumulation aging process. The loss of mitoprotease function (Stahl et al. 2002; Kambacheld et al. 2005; Fal- in these diseases impairs mitochondrial func- kevall et al. 2006; Mossmann et al. 2014; Taskin tion and causes metabolic-associated pheno- et al. 2017). types. In this review, we will focus on the close Mitoproteases mediating the processing of and often reciprocal relationship between mito- newly imported proteins often affect the subse- proteases and metabolic control. We will high- quent sorting of those proteins within mito- light the impact of mitoproteases on pathogen- chondria. For example, the inner mitochondrial esis and health span, a greater understanding of membrane peptidases (IMMPs) release soluble which may one day propel these enzymes for- proteins into the IMS by cleaving off their ward as therapeutic targets. hydrophobic sorting signals. The regulation of protein import and sorting by proteolysis therefore has a huge impact on mitochondrial metab- PROTEOLYSIS ORGANIZES THE olism, for instance by ensuring the assembly of MITOCHONDRIAL PROTEOME OXPHOS complexes to drive the generation of Mitochondria contain at least 20 intrinsic and ATP. Consequently, mutations in MPPs cause a catalytically functional proteases, which are di- number of diseases in humans, with neurode- vided into three catalytic classes: 12 metallopro- generative disorders being the most prevalent. teases, seven Ser proteases, and one Cys protease Mutation of either MPP subunit gene, PMPCA (Quiros et al. 2015). The intrinsic mitoproteases or PMPCB, causes similar early-onset neurolog- are distributed between the submitochondrial ical phenotypes in patients, with the cerebellum compartments in which they contribute to mi- being particularly affected (Jobling et al. 2015; tochondrial function and homeostasis by cleav- Choquet et al. 2016; Joshi et al. 2016; Vogtle et al. ing or completely degrading target substrates. A 2018). Mutations within PMPCB appear to pro- common feature of mitoproteases is their pleio- duce more severe symptoms, perhaps because tropic nature, which arises from the fact that a mutation of the catalytic subunit disturbs MPP protease may have multiple diverse substrates. processing activity to the greater extent (Vogtle The best examples of multisubstrate mitopro- et al. 2018). Furthermore, and to highlight the teases are those that regulate mitochondrial pro- range of diseases caused by processing peptidase tein import and biogenesis. defects, mutation of IMMP subunit 2–like pro- Newly synthesised mitochondrial proteins tease (IMMP2) is associated with developmental must be imported and sorted to the correct disorders such as Tourette syndrome, whereas mitochondrial subcompartment. The majority mutation of MIPEP, encoding the mitochondri- of these proteins contain an amino-terminal al intermediate peptidase (MIP/Oct1), causes targeting signal, or presequence, which can be infant heart failure (Petek et al. 2001; Bertelsen cleaved by a number of processing peptidases et al. 2014; Eldomery et al. 2016). Specific dis- located in the matrix or IMM. Arguably the eases associated with mitochondrial dysfunc- most common example is the essential and tion (broadly termed as mitochondriopathies) conserved mitochondrial-processing peptidase are also triggered by mutations in the pre- (MPP) complex, which is a heterodimer com- sequences of mitochondrial proteins. For exam- 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a033936 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Mitochondrial Proteolysis and Metabolic Control ple, impaired MPP processing of mutant Fra- tions that directly impact mitochondrial and taxin leads to disturbed iron homeostasis and cellular metabolic pathways. the neurodegenerative disorder Friedreich’s ataxia (Gakh et al. 2002), and a homozygous PROTEOLYTIC CONTROL OF mutation at the MPP-processing site of the pro- MITOCHONDRIAL RESPIRATION tease YME1L was recently found to impair mat- uration and destabilize the protein resulting in The production of ATP by OXPHOS can be neuropathy and optic atrophy (Hartmann et al. modulated by regulating the activities of meta- 2016). bolic enzymes, including the assembly of the Proteases can also modulate mitochondrial respiratory chain, the uptake of mitochondrial protein import by regulating components of the respiratory substrates, or by altering overall mi- import machinery. For instance, carboxy-termi- tochondrial mass. Nuclear and mitochondrial nal processing of the transmembrane protein gene expression and protein synthesis machin- Mgr2 by Imp (yeast IMMP) is required for ery must be synchronized and synergized to al- proper assembly and stabilization of the trans- low the synthesis and assembly of functional locase of inner mitochondrial membrane 23 OXPHOS complexes. Their coordination allows (Tim23/TIMM23) complex (Ieva et al. 2013). mitochondria to respond to ever-changing cel- Curiously, in comparison to yeast and fungal lular energy demands and substrate availability. Mgr2, the mammalian homolog ROMO1, Mitochondrial biogenesis, the maintenance of

Load more