Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis

Abstract

Mitochondria are multifunctional subcellular organelles essential for cellular energy homeostasis and apoptotic cell death. It is, therefore, crucial to maintain mitochondrial fitness. Mitophagy, the selective removal of dysfunctional mitochondria by autophagy, is critical for regulating mitochondrial quality control in many physiological processes, including cell development and differentiation. On the other hand, both impaired and excessive mitophagy are involved in the pathogenesis of different ageing-associated diseases such as neurodegeneration, cancer, myocardial injury, liver disease, sarcopenia and diabetes. The best-characterized mitophagy pathway is the PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent pathway. However, other Parkin-independent pathways are also reported to mediate the tethering of mitochondria to the autophagy apparatuses, directly activating mitophagy (mitophagy receptors and other E3 ligases). In addition, the existence of molecular mechanisms other than PINK1-mediated phosphorylation for Parkin activation was proposed. The adenosine5′-monophosphate (AMP)-activated protein kinase (AMPK) is emerging as a key player in mitochondrial metabolism and mitophagy. Beyond its involvement in mitochondrial fission and autophagosomal engulfment, its interplay with the PINK1–Parkin pathway is also reported. Here, we review the recent advances in elucidating the canonical molecular mechanisms and signaling pathways that regulate mitophagy, focusing on the early role and spatial specificity of the AMPK/ULK1 axis.

Regulation of Mitophagy by Sirtuin Family Proteins: A Vital Role in Aging and Age-Related Diseases

“…Then, the Ser228 and Ser402 residues of PINK1 are autophosphorylated, leading to the recruitment of Parkin to the mitochondrial membrane and activation of its E3 ubiquitin ligase activity (Nguyen et al, 2016a ). The ULK1 complex also is recruited to promote the recruitment of Parkin by PINK to the mitochondrial surface by phosphorylating Parkin at Ser108 (Iorio et al, 2021 ). The next autophagy adapters (p62/SQSTM1, NBR1, NDP52/CALCOCO2, TAX1BP1, and OPTN) play an important role.…”

Autophagy in asthma and chronic obstructive pulmonary disease

“…Autophagy plays a key role in maintaining normal mitochondrial function by detecting mitochondrial damage and removing there damaged organelles [ 12 ]. The best characterized mitophagy mechanism involves the serine/threonine kinase PINK1 (PTEN-induced putative kinase)-Parkin signaling pathway.…”

“…Several naturally occurring compounds have also been found to have autophagy modulating effects, including traditional Chinese herbal medicines used for asthma treatment [ 101 ]. Defective mitophagy may be targeted by autophagy activators, such as metformin and rapamycin, but also more specifically by drugs that activate the PINK1/Parkin pathway [ 12 ]. A recent study suggests that cannabidiol activates PINK1/Parkin signaling and increases mitophagy [ 102 ].…”

Atypical Ubiquitination and Parkinson’s Disease

“…The proteins related to PD, PINK1 (serine/threonine protein kinase) and parkin (E3 ubiquitin ligase), are the major players in mitophagy regulation. The mechanism of mitophagy has been considered in several recent reviews [ 151 , 153 , 154 ]. The role of post-translational modifications of proteins (particularly ubiquitination) in this cascade cannot be overestimated [ 132 ].…”