The role of Drp1 in mitophagy and cell death in the heart
Introduction
Mitochondria are highly abundant in the heart. Adult cardiac mitochondria comprise approximately 30% of the total cell volume and generate vast amounts of ATP through oxidative phosphorylation to maintain contractile function. Cardiomyocytes produce high levels of oxidative stress and are long-lived with infrequent, if not a complete absence of, proliferation [1]. To maintain mitochondrial homeostasis, cardiomyocytes have developed well-coordinated quality control mechanisms involving mitochondrial biogenesis, mitochondrial dynamics, and a mitochondria-specific form of autophagy, termed mitophagy [[2], [3], [4], [5]]. It has been suggested that mitochondrial fission and fusion serve as an early response to mitochondrial dysfunction, acting to overcome regional deterioration in mitochondria [6,7]. Mitochondria in adult cardiomyocytes are distributed in a more ordered fashion than in other cell types. They are located between myofibrils, around nuclei, and in the subsarcolemmal space, and are referred to as interfibrillar, perinuclear and subsarcolemmal mitochondria, respectively. In particular, intermyofibrillar mitochondria are located in parallel to and in direct contact with myofibers, thereby efficiently supplying ATP to myofibers. Due to this unique spatial organization, it has been speculated that their movement, including fusion, may be limited. Interestingly, however, recent evidence suggests that mitochondrial fusion is rather robust, supporting the exchange of matrix content between adjacent mitochondria in adult cardiomyocytes, which is controlled by cardiac contractility [8]. Furthermore, in mice in which Drp1, a dynamin-related GTPase that critically mediates fission, is downregulated in cardiomyocytes, mitochondria are elongated compared to in wild type mice. Thus, fission and fusion do take place in adult cardiomyocytes in vivo [9]. Our group has been investigating the molecular mechanisms responsible for mitochondrial quality control. In particular, we have focused on the role of Drp1 in the heart because the stressed heart contains fragmented mitochondria with mitochondrial translocation of Drp1 and because Drp1 plays an important role in mediating many aspects of mitochondrial quality control in the heart [9]. In this review, we will discuss the role of Drp1 in the heart.
Section snippets
General features of Drp1
Drp1 belongs to the dynamin family of GTP-binding proteins. The dynamin family includes Dnm1 in yeast and dynamin I, II, III in mammals. Classic Dynamin proteins contain a GTPase domain, a pleckstrin homology motif, and the proline-rich tail and mediate receptor-mediated endocytosis in organisms ranging from insects to vertebrates [10]. Dnm1 in yeast and Drp1 in mammals, which lack the pleckstrin homology motif and the proline-rich region, function in mitochondrial fission [11]. In humans, Drp1
The general autophagy pathway
Autophagy is an evolutionarily conserved “self-eating” process by which intracellular materials are degraded. The autophagy process begins with initiation and maturation of double-membraned vesicles called autophagosomes that enclose the materials to be degraded. Initiation is promoted by the unc-51-like autophagy-activating kinase (Ulk) complex (comprising Atg13, Ulk1, FIP200 and Atg101), which then activates another complex consisting of Beclin1, Atg14L, Vps34, and Vps15 for expansion of the
Apoptosis
Mitochondrial fragmentation is a conserved aspect of apoptosis from yeast, C.elegans, Drosophila to mammals [[59], [60], [61], [62], [63], [64]]. Since mitochondrial fragmentation is often observed when cells are under stress or when they are dying, Drp1 has been implicated in the pathogenesis of cell death [65]. For example, during apoptosis, activation of proapoptotic signaling BH3-only BIK induced mitochondrial cristae remodeling, loss of mitochondrial membrane potential and fragmentation,
The function of Drp1 in the heart
Homozygous deletion of Drp1 in mice leads to embryonic lethality between embryonic days (E) 9.5 and 11.5, with elongated mitochondria, reduced cell proliferation, and decreased developmentally regulated apoptosis [74]. Postnatal cardiac specific knock out of Drp1 induces dilated cardiomyopathy and rapid lethality in mice [9,47,75]. In Drp1KO cardiomyocytes, mitochondria exhibited increased connectivity, accumulation of ubiquitinated proteins, and decreased respiration [9,47,75]. These results
Concluding remarks
In this review we have discussed cellular functions of Drp1 with an emphasis on its role in mitochondrial quality control mechanisms and the pathophysiological roles of Drp1 in the heart. It is becoming clear that Drp1 influences the survival and death of cardiomyocytes, possibly through its fission-independent effects on mitophagy, apoptosis and respiration. However, further investigations are required to clarify whether the proposed cellular actions of Drp1, including mitophagy, apoptosis and
Funding
This work was supported in part by U.S. Public Health Service Grants HL67724, HL91469, HL112330, HL138720, HL144626, and AG23039 (J.S.), the American Heart Association 2020 Merit Award 20 Merit35120374 (J.S.), and by the Fondation Leducq Transatlantic Network of Excellence 15CBD04 (J.S).
Declaration of Competing Interest
The authors have declared that no conflict of interest exists.
Acknowledgements
None.
References (95)
- et al.
A role for the ancient SNARE syntaxin 17 in regulating mitochondrial division
Dev. Cell
(2015) - et al.
Mitochondria-specific function of the dynamin family protein DLP1 is mediated by its C-terminal domains
J. Biol. Chem.
(2004) - et al.
Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission
J. Biol. Chem.
(2007) - et al.
Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth
Mol. Cell
(2015) - et al.
Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology
J. Biol. Chem.
(2007) - et al.
Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission
Curr. Biol.
(2004) - et al.
Coincident phosphatidic acid interaction restrains Drp1 in mitochondrial division
Mol. Cell
(2016) - et al.
Dynamin-like protein 1 is involved in peroxisomal fission
J. Biol. Chem.
(2003) - et al.
The dynamin-like GTPase DLP1 is essential for peroxisome division and is recruited to peroxisomes in part by PEX11
J. Biol. Chem.
(2003) - et al.
Molecular mechanisms mediating mitochondrial dynamics and mitophagy and their functional roles in the cardiovascular system
J. Mol. Cell. Cardiol.
(2015)