At the Heart of Mitochondrial Quality Control: Many Roads to the Top

Cellular and Molecular Life Sciences https://doi.org/10.1007/s00018-021-03772-3 Cellular andMolecular Life Sciences REVIEW At the heart of mitochondrial quality control: many roads to the top Roberta A. Gottlieb1 · Honit Piplani1 · Jon Sin1 · Savannah Sawaged1 · Syed M. Hamid1 · David J. Taylor1 · Juliana de Freitas Germano1 Accepted: 8 January 2021 © The Author(s) 2021 Abstract Mitochondrial quality control depends upon selective elimination of damaged mitochondria, replacement by mitochondrial biogenesis, redistribution of mitochondrial components across the network by fusion, and segregation of damaged mitochondria by fssion prior to mitophagy. In this review, we focus on mitochondrial dynamics (fusion/fssion), mitophagy, and other mechanisms supporting mitochondrial quality control including maintenance of mtDNA and the mitochondrial unfolded protein response, particularly in the context of the heart. Keywords Mitochondria · Mitophagy · Fusion · Fission · Cardiac Introduction When the heart is stressed, mitochondria are frequently observed to change size and shape. The processes that medi- Mitochondrial quality control plays a key role in long-lived ate the fusion, fssion and fragmentation of mitochondria cells including cardiomyocytes and neurons. Non-dividing comprise mitochondrial dynamics, and a competent mito- cells require mechanisms to replace or repair proteins, com- chondrial dynamics system is essential for embryonic sur- plex assemblies of enzymatic machinery, and organelles, vival [1–3]. In general, mitochondria are regarded as existing as well as membranes and potentially even DNA. In this on a binary spectrum between two extremes of fusion and review, we will focus on mitochondria, while acknowledging fssion. The common designations ‘elongated/tubular/fused’ that repair/replacement mechanisms must also exist for other and ‘fragmented/fssed’ are typically employed to describe organelles including peroxisomes, lysosomes, endoplasmic these relative morphologic states, though more sophisticated reticulum, etc. While mitochondria are made up of protein descriptions also exist which incorporate interconnectedness assemblies, many of these are embedded in a lipid bilayer along with size. The functional consequences of a fused that requires ongoing maintenance, and uniquely, mitochon- mitochondrial network compared with a fragmented one are dria are the only organelle with their own genome; thus, poorly understood; however, much of what is known about the integrity of mitochondrial DNA (mtDNA) must also these morphologic states relates to how they interact with be maintained. In this review, we will focus primarily on the mitochondrial quality control machinery. mitophagy. Mitochondrial quality control involves selective elimination of damaged mitochondria, replacement by mitochondrial biogenesis, redistributing newly imported proteins Molecular regulation of mitochondrial across the mitochondrial network by fusion, and segregation dynamics of damaged portions of the mitochondrial network by fssion prior to mitophagy. The fusion/fssion machinery is composed of dynamin-like GTPase proteins which reside either in the cytoplasm or on the inner (IMM) and outer mitochondrial membranes (OMM). Dynamin-related protein 1 (Drp1, or DNM1L), * Roberta A. Gottlieb mainly located in the cytoplasm, is the principal efector [email protected] of fssion. Drp1 is activated by post-translational modifca- 1 Smidt Heart Institute, Cedars-Sinai Medical Center, tions and is recruited to mitochondria where it interacts with AHSP9313, 127 S. San Vicente Blvd., Los Angeles, resident OMM receptors Mf, MiD49 and MiD51 [4]. Active CA 90048, USA Vol.:(0123456789)1 3 R. A. Gottlieb et al. Drp1 undergoes oligomerization, leading to membrane con- homeostasis through the sequestration and subsequent elimi- striction with the process terminating with scission of the nation of damaged mitochondria by mitophagy. organelle mediated by Dynamin 2 [5]. Mitofusins 1 and 2 The OMM allows selective transport of metabolites and (Mfn1/2) are OMM resident GTPases, while Optic Atrophy connects the mitochondria to neighboring organelles. The 1 (Opa1) is located on the IMM. Collectively, they mediate IMM contains two separate compartments, the intermem- mitochondrial fusion, though their regulation and function brane space and the matrix, that are uniquely characterized are incompletely understood. One reason for this discrepancy by their cristae structures. The cristae provide the sites of the is that though a few target sites have been proposed, there are respiratory chain that are stabilized by the phospholipid car- no established mechanisms of post-translational regulation diolipin (CL) whose IMM binding is required for the func- of Mfn1/2 or Opa1, with the exception of proteolytic pro- tion of the ADP–ATP translocator, supercomplex stability, cessing of Opa1. Moreover, the distinction between fusion and cytochrome c oxidase [9, 10]. Under mitochondrial dys- and fssion apparatus is not cut and dried since although function, however, the CL pool undergoes signifcant change Opa1 is recognized as a fusion protein, it frequently partici- to alter mitochondrial dynamics and trigger mitophagy. CL pates in fragmentation when proteolytic degradation alters exhibits further structural roles within the IMM to increase its fusion activity [6]. One striking feature of mitochondrial mitochondrial size: genetic mutation of the cardiac and skel- dynamics is that mitochondrial networks can rapidly transi- etal muscle tafazzin results in 80% defciency of CL synthe- tion from a fused to a fragmented state in response to stress, sis and metabolism which is thought to contribute to cardio- while conditions that promote mitochondrial fusion lead to myopathy in Barth Syndrome patients [11]. CL defciency much slower morphologic changes. Acute mitochondrial is further observed to cause cristae disorganization within fragmentation is frequently observed under conditions of cardiomyocytes and fbroblasts, ultimately giving way to increased energy demands, following either physiological decreased CL biosynthesis and initiation of mitophagy or pathological stimuli in the exercising or ischemic heart, [12, 13]. In canonical mitophagy, CL serves as a signal for respectively [7, 8]. There are several theories which may autophagic proteins to recognize dysfunctional mitochondria explain why more active mitochondria undergo fragmen- for degradation [14]. The mechanism of CL exposure from tation. We have speculated that fragmentation may serve the IMM to OMM for cytosolic protein recognition remains to increase surface area for nutrient and oxygen exchange, in question, whether CL is translocated or perhaps external- which will facilitate respiration—analogous to breaking up ized to the OMM during mitophagy. a long banquet table into smaller tables which increases the One mechanism proposed for CL remodeling is the trans- available seating. Alternatively, if membrane surface area location of CL by phospholipid scramblases (PLS) that is held constant during fragmentation, matrix volume will mediate translocation of phospholipids between the mem- decrease, potentially elevating concentration of key solutes brane bilayer. PLSCR3 is specifcally enriched in the IMM including Ca+2 (Fig. 1). Another intriguing hypothesis is that and is important for maintenance of mitochondrial mass heat generated by active mitochondria poses a thermal stress and respiration, yet is also required for sensitivity for cyt to these organelles, and that by increasing the mitochondrial c release and CL mobilization [15]. UV irradiation nearly membrane surface area in contact with cytosol, this ther- doubles the amount of CL on the OMM in a model of WT mal energy can be more rapidly dissipated. Finally, there vs. mutant PLSCR3 HEK293 cells, suggesting that PLSCR3 exists a large body of data to support a role for mitochondrial facilitates CL transport. Another IMM protein NDPK-D has fssion as a key step in the process of maintaining cellular recently been demonstrated to facilitate CL mobilization upon mitochondrial uncoupling with CCCP in murine lung epithelial cells and human HeLa cells [16]. Interestingly, Kagan et al. discovered a novel interaction of NDPK-D with OPA1, implicating a close relationship of fssion–fusion in PLS-mediated CL translocation. Another proposed mechanism of exposure of CL is through OMM pores formed by Bax/tBid interaction [17, 18]. Evidence for membrane permeabilization by these apoptosis family member proteins comes from a combi- nation of studies using mutagenesis [19], surface plasmon resonance [20], and glycosylation mapping [21] to deter- mine the precise membrane-binding interactions. Specif- cally, during apoptosis, proteolysis of Bid by caspase-8 [22] or calpain [23] generates the active truncated form of Bid Fig. 1 Surface area: volume relationship in mitochondria (tBid). The processed tBid interacts with Bax to promote 1 3 At the heart of mitochondrial quality control: many roads to the top the formation of pore-like structures in the OMM, enabling mitochondrion from rejoining the network. It follows that cytochrome c release from the IMM and potentially allowing during fusion, or in the interval between fssion events, mito- cytosolic proteins to interact with CL on the inner mem- chondria sequester their healthy or damaged components to brane [24]. This can be amplifed through a feedback cycle opposing poles of the mitochondria. Asymmetric fssion of of CL interaction

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