Regulation of mitophagy by the ubiquitin pathway in neurodegenerative diseases

Mitophagy is a cellular process by which dysfunctional mitochondria are degraded via autophagy. Increasing empirical evidence proposes that this mitochondrial quality-control mechanism is defective in neurons of patients with various neurodegenerative diseases such as Ataxia Telangiectasia, Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Accumulation of defective mitochondria and the production of reactive oxygen species due to defective mitophagy have been identified as causes underlying neurodegenerative disease pathogenesis. However, the reason mitophagy is defective in most neurodegenerative diseases is unclear. Like mitophagy, defects in the ubiquitin/26S proteasome pathway have been linked to neurodegeneration, resulting in the characteristic protein aggregates often seen in neurons of affected patients. Although initiation of mitophagy requires a functional ubiquitin pathway, whether defects in the ubiquitin pathway are causally responsible for defective mitophagy is not known. In this mini-review, we introduce mitophagy and ubiquitin pathways and provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway. We will then briefly review empirical evidence supporting mitophagy defects in neurodegenerative diseases. The review will conclude with a discussion of the constitutively elevated expression of ubiquitin-like protein Interferon-Stimulated Gene 15 (ISG15), an antagonist of the ubiquitin pathway, as a potential cause of defective mitophagy in neurodegenerative diseases. Impact statement Neurodegenerative diseases place an enormous burden on patients and caregivers globally. Over six million people in the United States alone suffer from neurodegenerative diseases, all of which are chronic, incurable, and with causes unknown. Identifying a common molecular mechanism underpinning neurodegenerative disease pathology is urgently needed to aid in the design of effective therapies to ease suffering, reduce economic cost, and improve the quality of life for these patients. Although the development of neurodegeneration may vary between neurodegenerative diseases, they have common cellular hallmarks, including defects in the ubiquitin-proteasome system and mitophagy. In this review, we will provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway and discuss the potential of targeting mitophagy and ubiquitin pathways for the treatment of neurodegeneration.