Abstract
The normal function of the mitochondria is crucial for most tissues especially for those that demand a high energy supply. Emerging evidence has pointed out that healthy mitochondrial function is closely associated with normal heart function. When these processes fail to repair the damaged mitochondria, cells initiate a removal process referred to as mitophagy to clear away defective mitochondria. In cardiomyocytes, mitophagy is closely associated with metabolic activity, cell differentiation, apoptosis, and other physiological processes involved in major phenotypic alterations. Mitophagy alterations may contribute to detrimental or beneficial effects in a multitude of cardiac diseases, indicating potential clinical insights after a close understanding of the mechanisms. Here, we discuss the current opinions of mitophagy in the progression of cardiac diseases, such as ischemic heart disease, diabetic cardiomyopathy, cardiac hypertrophy, heart failure, and arrhythmia, and focus on the key molecules and related pathways involved in the regulation of mitophagy. We also discuss recently reported approaches targeting mitophagy in the therapy of cardiac diseases.
Highlights
Mitochondrial metabolism is important to supply a tremendous energy demand for the heart [1]
Mitophagy receptors are principally localized on the outer mitochondrial membrane (OMM) via transmembrane domains and attach autophagosomes to the mitochondria through the Light Chain 3 (LC3)-interacting region (LIR) motif, including ATG32 in yeast, B-cell CLL/lymphoma 2- (BCL2-) interacting protein 3 (BNIP3), BCL2/adenovirus E1B kDa-interacting protein 3 (BNIP3)-like (BNIP3L)/NIX, FUN14 domain-containing 1 (FUNDC1), Bcl2-like 13 (BCL2L13), and FKBP prolyl isomerase 8, in mammalian cells [27]
Choline dehydrogenase (CHDH) accumulates in the OMM in response to damaged mitochondrial potential, which is normally localized in IMM and OMM
Summary
Mitochondrial metabolism is important to supply a tremendous energy demand for the heart [1]. Mitophagy receptors are principally localized on the outer mitochondrial membrane (OMM) via transmembrane domains and attach autophagosomes to the mitochondria through the LC3-interacting region (LIR) motif, including ATG32 in yeast, B-cell CLL/lymphoma 2- (BCL2-) interacting protein 3 (BNIP3), BNIP3-like (BNIP3L)/NIX, FUN14 domain-containing 1 (FUNDC1), Bcl2-like 13 (BCL2L13), and FKBP prolyl isomerase 8, in mammalian cells [27]. These mitophagy receptors recruit ATG8 family protein LC3 and its homolog gammaaminobutyric acid receptor-associated protein to the mitochondrial membrane and induce the initiation of mitophagy independent of the ubiquitin pathway with the aid of the LIR motif [27]. Cargo-binding receptors (LC3 adaptors) can be recognized by LC3 and recruited to polyubiquitinated substrates on the mitochondria through their ubiquitin-binding domain, including sequestosome-1 (p62), nuclear domain 10 protein 52, optineurin, Trans-activating transcriptional regulatory protein of HTLV-1-binding protein 1, and neighbor of breast cancer 1 gene 1 [43]
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