Elsevier

Mitochondrion

Volume 49, November 2019, Pages 289-304
Mitochondrion

Review
Proteolytic regulation of mitochondrial dynamics

https://doi.org/10.1016/j.mito.2019.04.008Get rights and content

Abstract

Spatiotemporal changes in the abundance, shape, and cellular localization of the mitochondrial network, also known as mitochondrial dynamics, are now widely recognized to play a key role in mitochondrial and cellular physiology as well as disease states. This process involves coordinated remodeling of the outer and inner mitochondrial membranes by conserved dynamin-like guanosine triphosphatases and their partner molecules in response to various physiological and stress stimuli. Although the core machineries that mediate fusion and partitioning of the mitochondrial network have been extensively characterized, many aspects of their function and regulation are incompletely understood and only beginning to emerge. In the present review we briefly summarize current knowledge about how the key mitochondrial dynamics-mediating factors are regulated via selective proteolysis by mitochondrial and cellular proteolytic machineries.

Introduction

Mitochondrial dynamics is a process that can be defined as spatiotemporal changes in mitochondrial shape, number and position within the cell. These changes occur in response to various stimuli and conditions and comprise reciprocal events known as mitochondrial fragmentation (fission) and fusion of mitochondrial network. Proper balance between fission and fusion events is necessary to maintain appropriate mitochondrial functions including, but not limited to energy conversion, cofactor and metabolite synthesis, ion homeostasis maintenance, cell signaling, differentiation and death (Scheffler, 2007; Scott and Youle, 2010; Twig and Shirihai, 2011; Zhong et al., 2018). Disruption of these dynamic events prompts mitochondria-linked neurodegeneration, neuropathies, cardiovascular disorders, myopathies, certain cancers, and metabolic disorders (Anzell et al., 2018; Bohovych et al., 2015; Levytskyy et al., 2016; Panchal and Tiwari, 2018; Scheffler, 2007; Trotta and Chipuk, 2017).

Mitochondria harbor two sets of membranes – the outer (OM) and the inner (IM) mitochondrial membranes, the fusion and division of which are coordinated but physically separate processes (Malka et al., 2005), each of which requires complex multi-component machinery. Moreover, molecular events in the IM appear to precede and overpower ones that involve the OM (Ban et al., 2017; Chakrabarti et al., 2018; Cho et al., 2017; Song et al., 2009). Although new regulatory mechanisms and molecules are still being discovered, the key factors behind mitochondrial dynamics have been well characterized (Fig. 1A). The mammalian mitochondrial dynamin-like guanosine triphosphatases (GTPases) mitofusin 1 and 2 (Mfn1/2) (Fig. 1B) direct OM fusion by forming GTP-dependent homo- and heterotypic complexes linking adjacent mitochondria (Chen et al., 2005; Chen et al., 2003; Franco et al., 2016; Huang et al., 2017; Ishihara et al., 2004; Koshiba et al., 2004; Mattie et al., 2018). Mitofusins are conserved proteins with robust homologs present in Saccharomyces cerevisiae and Schizosaccharomyces pombe (Fzo1), Caenorhabditis elegans (FZO-1), and Drosophila melanogaster (FZO and DMFN) (reviewed in Westermann, 2010a). Numerous post-translational modifications, ubiquitylation in particular, regulate mitofusins' activity and can target them for ubiquitin proteasome system (UPS)-mediated degradation (Ali and McStay, 2018; Wai and Langer, 2016). Regulation by ubiquitylation and proteasomal degradation of mitofusins is an evolutionarily conserved process.

In mammals, OM fission is completed by the dynamin-related protein GTPase Drp1 (Fig. 1). Specific cellular signals induce Drp1 to localize to the mitochondria at a future site of division (Cereghetti et al., 2008; Chang and Blackstone, 2007a; Chang and Blackstone, 2010b; Cribbs and Strack, 2007; Ji et al., 2015; Kashatus et al., 2015; Prieto et al., 2016). Upon translocation to the mitochondria, the OM fission factor self-oligomerizes and forms a ring-like structure around the organelle. Adaptor proteins (Fis1, Mff, MiD49, MiD51) are necessary to link the Drp1-ring to the mitochondria at the site of fission. GTP hydrolysis by Drp1 causes the ring-like structure to constrict until fragmentation is completed (Otera et al., 2013; Otera and Mihara, 2011; Wai and Langer, 2016). An OM fission factor structurally and mechanistically similar to Drp1 has been described in other eukaryotes including S. cerevisiae (Dnm1), C. elegans (DRP-1), and D. melanogaster (DRP1). However, the mitochondrial adaptor proteins necessary for Drp1-ring tethering are not nearly as conserved (Westermann, 2010a). Currently, known homologs for Fis1 have been identified in S. cerevisiae (Fis1), C. elegans (FIS-1/2), and D. melanogaster (FIS1), and an Mff-like homolog has been described in D. melanogaster (reviewed by Westermann, 2010a). In S. cerevisiae, additional OM fission adaptor proteins were identified as Mdv1 and Caf4 (Griffin et al., 2005; Ingerman et al., 2005; Tieu et al., 2002; Tieu and Nunnari, 2000). Mammalian Drp1 stability and activity are regulated by phosphorylation and by ubiquitylation and UPS-mediated degradation in an E3 ubiquitin ligase Parkin-dependent manner (Tang et al., 2016; Wang et al., 2011a). The mechanisms behind the turnover of Drp1 homologs remain to be clarified. It should be noted that regulation of OM fission adaptor proteins does not appear to be a conserved process. Only the yeast adaptor Mdv1 is identified as a target for ubiquitylation and UPS-mediated degradation by an unknown E3 ubiquitin ligase (Christiano et al., 2014; Swaney et al., 2013).

Opa1, a GTPase anchored to the IM, functions as the mediator of IM fusion (Fig. 1). Canonically, mammalian Opa1 exists at its full length (L-Opa1) and promotes mitochondrial fusion, but upon specific homeostatic stimuli, it is cleaved producing a short form (S-Opa1). Accumulation of S-Opa1 results in mitochondrial fission transitioning Opa1 into an IM fission factor (Del Dotto et al., 2018a; Wai and Langer, 2016). The factor is highly conserved with known homologs in S. cerevisiae (Mgm1), S. pombe (msp1), C. elegans (EAT-3), and D. melanogaster (OPA1). However, maturation and regulation of these proteins via proteolysis has significantly diverged.

As such, complex and differential machineries mediate changes in the IM and OM dynamics in response to various stimuli. The IM dynamics is a subject of the proteolytic control by the enzymes intrinsic to the compartment, whereas the OM division and fusion are regulated by the UPS-mediated degradation of the OM fusion factors or relevant adaptor proteins.

Mitochondrial dynamics-mediated morphological and ultrastructural changes, as well as their role in maintaining mitochondrial homeostasis, are evolutionarily conserved. Studies in fungal, mammalian cell culture and murine models indicate that specific proteases and the ubiquitin proteasome system are imperative in regulating the proteins necessary for efficient mitochondrial fusion and fission. In the present review, we will discuss various mechanisms involved in proteolytic regulation of OM and IM fusion and division factors.

Section snippets

The OM fusion factors mitofusin/Fzo1 and Miro/Gem1

Proteolytic processing plays an important role in the regulation of the OM-localized GTPases mitofusins 1 and 2 (Mfn1/2 in mammals, Fzo1 in yeast) that are central to OM fusion (Wai and Langer, 2016). Likewise, yeast Fzo1 is central to mitochondrial fusion and normal mitochondrial morphology, and its deficiency induces mitochondrial fragmentation, mtDNA loss, and petite colony formation (Hermann et al., 1998; Rapaport et al., 1998). It is noteworthy, however, that multiple studies have unveiled

The IM fusion factor Opa1/Mgm1

The fusion and division dynamics of the IM are primarily controlled via proteolytic processing of the dynamin-like GTPase Opa1 (Baker et al., 2014; Ishihara et al., 2006; Saita et al., 2016). This pro-fusion factor was originally associated with the dominantly inherited progressive vision loss Optic atrophy type 1 (Alexander et al., 2000; Delettre et al., 2000), hence the name. Within the last two decades more than 370 mutations in the human OPA1 gene causing neurological disorders of various

Concluding remarks

A well-tuned and timely regulation of the mitochondrial network morphology is critical for responses to various stimuli and adaptation to both normal and stress conditions. Deregulated mitochondrial dynamics has been associated with severe, often detrimental, effects on cellular physiology and fate and has now emerged as an important factor behind a large number of human pathologies. Although the core machineries that mediate fusion and partitioning of mitochondrial network have been

Conflicts of interest

The authors declare no competing or financial interests.

Acknowledgments

We apologize to those authors whose work we were unable to cite due to space limitations. We thank the members of Khalimonchuk lab and Dr. Jennifer Fox (College of Charleston) for insightful comments and editorial help. We thank Carey Goddard for her expert help with figures preparation. We acknowledge support from the U.S. National Institutes of Health (R01 GM108975 to O.K. and T32 GM107001-01A1 to J.V.D.).

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