Mitochondrial dynamics in cardiovascular health and disease

Abstract

Significance: Mitochondria are dynamic organelles capable of changing their shape and distribution by undergoing either fission or fusion. Changes in mitochondrial dynamics, which is under the control of specific mitochondrial fission and fusion proteins, have been implicated in cell division, embryonic development, apoptosis, autophagy, and metabolism. Although the machinery for modulating mitochondrial dynamics is present in the cardiovascular system, its function there has only recently been investigated. In this article, we review the emerging role of mitochondrial dynamics in cardiovascular health and disease.

Recent advances: Changes in mitochondrial dynamics have been implicated in vascular smooth cell proliferation, cardiac development and differentiation, cardiomyocyte hypertrophy, myocardial ischemia-reperfusion injury, cardioprotection, and heart failure.

Critical issues: Many of the experimental studies investigating mitochondrial dynamics in the cardiovascular system have been confined to cardiac cell lines, vascular cells, or neonatal cardiomyocytes, in which mitochondria are distributed throughout the cytoplasm and are free to move. However, in the adult heart where mitochondrial movements are restricted by their tightly-packed distribution along myofibrils or beneath the subsarcolemma, the relevance of mitochondrial dynamics is less obvious. The investigation of transgenic mice deficient in cardiac mitochondrial fission or fusion proteins should help elucidate the role of mitochondrial dynamics in the adult heart.

Future directions: Investigating the role of mitochondrial dynamics in cardiovascular health and disease should result in the identification of novel therapeutic targets for treating patients with cardiovascular disease, the leading cause of death and disability globally.

FIG. 1.

Representative confocal images of HL-1 cardiac cells transfected with mitochondrial red fluorescent protein depicting (A) a cell displaying relatively fragmented mitochondria following mitochondrial fission, and (B) a cell displaying relatively elongated mitochondria following mitochondrial fusion. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Simplified scheme depicting the processes of: (left) mitochondrial fission, which is mediated by the mitochondrial fission proteins, Drp1, MFF, MiD49/51, and hFis1, and generates fragmented mitochondria; (right) mitochondrial fusion, which is mediated by the mitochondrial fusion proteins, OPA1, Mfn1, and Mfn2, and generates elongated mitochondria. In mitochondrial fission, cytosolic Drp1 translocates to the outer mitochondrial membrane, a process which is facilitated by MFF, Mid49/51, and hFis1 (the actual details and interplay between these proteins remain unclear). The Drp1 then self-assembles and form helices that encircle the dividing mitochondria to mediate scission of the mitochondria. The divided mitochondria can then enter the fusion–fission cycle, or if the mitochondria are damaged (mitochondria membrane depolarization) then these fragmented mitochondria are removed by the process of mitophagy. In mitochondrial fusion, Mfn1 and Mfn2 on the OMM tether adjacent mitochondria and mediate fusion of the OMM, which is then followed by IMM fusion mediated by OPA1. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Representative electron micrograph of the adult murine heart depicting the 3 subpopulations of mitochondria: (1) Interfibrillar mitochondria (IFM); (2) Perinuclear mitochondria (PNM); and (3) Subsarcolemmal mitochondria (SSM).

FIG. 4.

Representative electron micrograph of adult murine heart depicting: (A) mitochondria of normal lengths of 1–2 μm (one or two mitochondria per sarcomere); (B) elongated mitochondria extending up to 3–4 sarcomeres in length (6–8 μm), suggesting that under basal conditions mitochondria are able to undergo end-to-end fusion.

FIG. 5.

Representative electron micrograph of adult murine heart depicting fragmented mitochondria, disorganized cristae, and disrupted sarcomeres following an episode of sustained ischemia (20 min).

FIG. 6.

Representative confocal image of HL-1 cardiac cells transfected with mitochondrial red fluorescent protein depicting the formation of toroidal (‘donut’) shaped mitochondria following an episode of simulated ischemia. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars