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Review
. 2015 May 22;116(11):1835-49.
doi: 10.1161/CIRCRESAHA.116.306374.

How mitochondrial dynamism orchestrates mitophagy

Orian S Shirihai  1 , Moshi Song  1 , Gerald W Dorn 2nd  2
Affiliations
Review

How mitochondrial dynamism orchestrates mitophagy

Orian S Shirihai et al. Circ Res. .

Abstract

Mitochondria are highly dynamic, except in adult cardiomyocytes. Yet, the fission and fusion-promoting proteins that mediate mitochondrial dynamism are highly expressed in, and essential to the normal functioning of, hearts. Here, we review accumulating evidence supporting important roles for mitochondrial fission and fusion in cardiac mitochondrial quality control, focusing on the PTEN-induced putative kinase 1-Parkin mitophagy pathway. Based in part on recent findings from in vivo mouse models in which mitofusin-mediated mitochondrial fusion or dynamin-related protein 1-mediated mitochondrial fission was conditionally interrupted in cardiac myocytes, we propose several new concepts that may provide insight into the cardiac mitochondrial dynamism-mitophagy interactome.

Keywords: Parkinson disease; autophagy; mitochondria; mitochondrial dynamics.

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Figures

Figure 1
Figure 1. Sausage link model of mitochondrial fission by Drp1
Top, schematic depiction of Drp1 molecular structure. The GTPase domain (green) is at the amino terminus and the GTPase-effector domain (GED; rust) is at the carboxyl terminus. The GED interacts with the middle domain of adjacent molecules (dashed lines) to promote head-to-toe oligomerization. GTP-mediated constriction of oligomeric ring structures constricts and severs the mitochondrion like forming sausage links (bottom). Sites for some post-translational modifications are represented on the uppermost structure; P is phosphorylation, NO is S-nitrosylation, SUMO is sumoylation.
Figure 2
Figure 2. Turducken model of mitochondrial structure and fusion by Mfn1, Mfn2, and Opa1
Top, multi-compartment structure of turducken (left) and cartoon mitochondrion (right). Outer mitochondrial membrane (OMM) fusion protein mitofusins (Mfn) 1 or 2 and inner mitochondrial membrane (IMM) fusion protein Opa1 are shown with GTPase domains in green. Exploded view of electron transport chain and associated pathways is bottom right. Bottom left, schematic depiction of Mfn-Mfn binding in trans, tethering two mitochondria; inset is authors’ conception of how pro-fission protein Drp1 (blue) may facilitate Mfn-mediated fusion.
Figure 3
Figure 3. Replicative and asymmetric fission and intra-organelle partitioning of damaged components
Left; diagram of symmetric replicative fission (top) and asymmetric fission leading to selective mitophagy of the impaired daughter organelle (bottom). Right; illustration with Lego blocks of how misfolded proteins (front right) might passively segregate from functioning respiratory supercomplexes (rear left).
Figure 4
Figure 4. Molecular events leading to selective mitophagy of dysfunctional mitochondria
Left; mitochondrial depolarization or other impairment interrupts normal proteolytic processing of PINK1 kinase. PINK1 accumulates on the OMM and phosphorylates Mfn2, promoting its recruitment of Parkin, and ubiquitin (Ub), enabling its utilization by Parkin. Poly-ubiquitinated OMM proteins bind p62 linked to autophagosomal LC3, thus targeting the mitochondrion for mitophagy.
Figure 5
Figure 5. Mechanisms of mitochondrial quality improvement, from macro to micro
At the top is PINK1/Parkin-mediated mitophagy of an intact organelle, as with the depolarized daughter of an asymmetric fission event (see Figure 3). To the left is bit-by-bit autophagy of localized mitochondrial damage, which is excised and engulfed by an autophagosome via Parkin activity. At the bottom is PINK1/Parkin-mediated formation of mitochondria-derived vesicle, incorporating damaged components into a vesicle that transports them to lysosomes. On the right is shown PINK1-Parkin independent proteasomal removal of outer mitochondrial membrane proteins, and protease-dependent degradation of internal mitochondrial proteins, the most selective of the quality improvement processes.
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