Mitophagy in neurological disorders

Abstract

Selective autophagy is an evolutionarily conserved mechanism that removes excess protein aggregates and damaged intracellular components. Most eukaryotic cells, including neurons, rely on proficient mitophagy responses to fine-tune the mitochondrial number and preserve energy metabolism. In some circumstances (such as the presence of pathogenic protein oligopolymers and protein mutations), dysfunctional mitophagy leads to nerve degeneration, with age-dependent intracellular accumulation of protein aggregates and dysfunctional organelles, leading to neurodegenerative disease. However, when pathogenic protein oligopolymers, protein mutations, stress, or injury are present, mitophagy prevents the accumulation of damaged mitochondria. Accordingly, mitophagy mediates neuroprotective effects in some forms of neurodegenerative disease (e.g., Alzheimer's disease, Parkinson’s disease, Huntington's disease, and Amyotrophic lateral sclerosis) and acute brain damage (e.g., stroke, hypoxic–ischemic brain injury, epilepsy, and traumatic brain injury). The complex interplay between mitophagy and neurological disorders suggests that targeting mitophagy might be applicable for the treatment of neurodegenerative diseases and acute brain injury. However, due to the complexity of the mitophagy mechanism, mitophagy can be both harmful and beneficial, and future efforts should focus on maximizing its benefits. Here, we discuss the impact of mitophagy on neurological disorders, emphasizing the contrast between the positive and negative effects of mitophagy.

Overexpression of NAF-1 ameliorates Ischemic Stroke in rats by inhibiting PINK1/Parkin-mediated mitophagy

“…Mitophagy is a dynamic process that removes damaged mitochondria by autophagy. The process of autophagy includes the formation of phagophores, the maturation of bilayer structures, and the fusion and degradation of autophago-lysosomes [5,26]. The conversion of LC3I to LCII and the degradation of the latter are key events in the autophagy process [27].…”

“…In neurons, mitochondrial oxidative phosphorylation is the primary source of ATP [5]. During the reperfusion stage following stroke, reactive oxygen species are produced in large quantities, resulting in mitochondrial dysfunction [6].…”

Antimicrobial peptides with cell-penetrating activity as prophylactic and treatment drugs

“…Consequently, it has been observed that genetic mutations affecting autophagic genes promote cellular degeneration [ 103 , 104 ], promote early-age-related phenotypes [ 105 , 106 ], tumor development [ 107 , 108 ], and susceptibility to infections in animals [ 109 , 110 ]. Similarly, mutations of genes related to autophagy are present in several Mendelian diseases in humans such as Rett’s syndrome, Parkinson’s disease, cataracts, several forms of cardiomyopathies, among others [ 111 ].…”

Miro proteins and their role in mitochondrial transfer in cancer and beyond

“…Dysregulation of mitophagy (and calcium signaling) is linked to many pathologies, starting with neurological diseases such as Parkinson disease (PD), heart failure, metabolic disorders, aging and cancer ( Lahiri and Klionsky, 2017 ; Kay et al, 2018 ; Pickles et al, 2018 ; Cao et al, 2019 ; Kesharwani et al, 2019 ; Berenguer-Escuder et al, 2020 ; Brunelli et al, 2020 ; Eberhardt et al, 2020 ; Imai, 2020 ; Denisenko et al, 2021 ; Nahacka et al, 2021 ; Zhang et al, 2021 ; Babula and Krizanova, 2022 ; Diao and Gustafsson, 2022 ; Lee et al, 2022 ; Shan et al, 2022 ). Miro proteins are important regulators of the process of mitophagy, firstly prior to mitochondrial damage where they serve as calcium sensors, translocating Parkin to mitochondria, and then as Parkin downstream targets where ubiquitination of Miro proteins arrests mitochondrial trafficking needed for the organelle removal ( Nahacka et al, 2021 ).…”