Mitochondrial quality control in health and cardiovascular diseases

Abstract

Cardiovascular diseases (CVDs) are one of the primary causes of mortality worldwide. An optimal mitochondrial function is central to supplying tissues with high energy demand, such as the cardiovascular system. In addition to producing ATP as a power source, mitochondria are also heavily involved in adaptation to environmental stress and fine-tuning tissue functions. Mitochondrial quality control (MQC) through fission, fusion, mitophagy, and biogenesis ensures the clearance of dysfunctional mitochondria and preserves mitochondrial homeostasis in cardiovascular tissues. Furthermore, mitochondria generate reactive oxygen species (ROS), which trigger the production of pro-inflammatory cytokines and regulate cell survival. Mitochondrial dysfunction has been implicated in multiple CVDs, including ischemia-reperfusion (I/R), atherosclerosis, heart failure, cardiac hypertrophy, hypertension, diabetic and genetic cardiomyopathies, and Kawasaki Disease (KD). Thus, MQC is pivotal in promoting cardiovascular health. Here, we outline the mechanisms of MQC and discuss the current literature on mitochondrial adaptation in CVDs.

Keywords: ROS; cardiovascular disease; mitobiogenesis; mitochondria; mitochondrial dynamics; mitophagy.

FIGURE 1

Mitochondrial structure. Mitochondria are double-membraned organelles with cristae formation. Mitochondria functioning is central for bioenergetic activities, producing ATP, an important source of ROS production. Mitochondria have several channels and pores to allow for metabolite and protein import, pivotal for inter-organelle communication. Part of ETC subunits are encoded in mitochondria’s circular DNA, named mtDNA. TCA cycle that produces important electron carriers for ETC, as well as ATP, and resides on the IMM. mtROS, mitochondrial reactive oxygen species; ETC, electron transport chain; mtDNA, mitochondrial DNA; IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; mPTP, mitochondrial permeability transition pore; VDAC, voltage-dependent anion channel.

FIGURE 2

Schematic of mitochondria electron transport chain (ETC) and Oxidative phosphorylation (OXPHOS). ETC comprises four complexes that reside in the inner mitochondrial membrane that leads to the production of ATP. The TCA cycle is the source of NADH and FADH_2, which are required for electron transport between the complexes, finalized by the production of ATP at the last step.

FIGURE 3

Mitochondrial quality control (MQC) mechanisms. The master regulator of mitochondrial biogenesis is PGC-1α, which induces NRF1, NRF2, and TFAM expression in the nucleus. Mitochondria life cycle includes fusion, which forms elongated mitochondrial networks, and fission, which creates fragmented mitochondria. MFN1, MFN2, and OPA1 are responsible for the membrane fusion of mitochondria, whereas DRP1, FIS1, and MFF mediate fission. Mitochondria accumulate oxidative damage during their expected lifespan or in the case of CVDs. Fission enables the fragmentation of damaged mitochondria to be separated and degraded. The elimination of damaged mitochondria is achieved via mitophagy, initiated by the accumulation of PINK1 kinase in the mitochondrial membrane, followed by the recruitment of Parkin, which targets the mitochondria to the autophagosome. p62 targets the mitochondria to the autophagosome and is eliminated during active autophagy. Assembly of the autophagosome requires Beclin1 and attachment of LC3-I onto phosphatidylethanolamine to form LC3-II.

FIGURE 4

Mechanisms of mitophagy. (A) PINK1/Parkin-dependent mitophagy. PINK1 accumulates on damaged mitochondria and recruits Parkin to promote the ubiquitination of OMM proteins. Poly-ubiquitin chains provide an eat me signal to initiate autophagy. TBK1 phosphorylates OPTN and NDP52 to induce clearance of damaged mitochondria. (B) Parkin-independent mitophagy pathways, (1) BNIP3/FUNDC1 mediated and (2) lipid-mediated mitophagy. Mitophagy receptors BNIP3 and FUNDC1 favor mitochondrial fission via DRP1 interaction and OPA1 release.