Mitochondrial Quality Control in Cardiac Diseases

Abstract

Disruption of mitochondrial homeostasis is a hallmark of cardiac diseases. Therefore, maintenance of mitochondrial integrity through different surveillance mechanisms is critical for cardiomyocyte survival. In this review, we discuss the most recent findings on the central role of mitochondrial quality control processes including regulation of mitochondrial redox balance, aldehyde metabolism, proteostasis, dynamics, and clearance in cardiac diseases, highlighting their potential as therapeutic targets.

Keywords: 4-hydroxynonenal; aldehyde dehydrogenase 2; bioenergetics; fusion-fission balance; mitochondrial unfolded protein response; mitophagy; oxidative stress.

Figure 1

(A) Reactive aldehydes in mitochondria: excessive reactive oxygen species causes lipid peroxidation and consequent generation of 4-hydroxynonenal (4-HNE), a highly reactive aldehyde that readily forms protein adducts. Accumulation of 4-HNE adducts causes mitochondrial dysfunction and contributes to the propagation of stress related to cardiac pathophysiology. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme responsible for the conversion of 4-HNE into inactive acids. (B) Mitochondrial unfolded protein response (UPR^mt): Accumulation of mitochondrial unfolded proteins results in increased proteolysis and release of mitochondrial-generated peptides to the cytosol. It is suggested that these peptides activate cytosolic transcription factors (i.e., ATFS-1, UBL-5, and DVE-1). Once inside the nucleus, these transcription factors promote upregulation of genes involved in mitochondrial proteostasis (i.e., chaperones and proteases), thus relieving stress and re-establishing mitochondrial homeostasis. The UPR^mt has been characterized in the nematode Caenorhabditis elegans.

Figure 2

(A) Mitochondrial fusion-fission balance: Mitochondrial fission: Drp1 translocates to mitochondria and binds to Fis1 to promote fission. Daughter mitochondria can be recovered or removed. Recovered mitochondria re-enter in the life cycle to fuse with healthy mitochondria. Mitochondrial fusion: outer membrane fusion is regulated by Mfn1 and Mfn2, while OPA1 is responsible for inner mitochondrial membrane fusion. (B) Mitophagy: damaged mitochondria can be sequestered by autophagosomes. The autophagosomes then fuse with lysosomes to degrade sequestered mitochondria.