The role of phospho-ubiquitin in mitochondrial health and diseases.

Mitochondria play a major role in cellular health, yet their contribution to chronic diseases has been underestimated. Mitochondria are essential for all tissues and are the major source of ATP in high-energy-demand organs such as brain and heart, which consequently are vulnerable to mitochondrial dysfunction. Failure to repair or remove damaged mitochondria contributes to aging and chronic diseases. Cells have evolved quality control mechanisms, including mitophagy to eliminate damaged mitochondria and mitobiogenesis to replenish them. The ubiquitin-proteasome system (UPS) is responsible for removing misfolded proteins, a process that is highly ATP dependent and therefore reliant on mitochondrial function. In turn, damaged mitochondria are eliminated through coordinated actions of the UPS and lysosomal degradation through mitophagy. Many neurodegenerative diseases are characterized by the presence of disease-specific protein aggregates, such as α-synuclein aggregates in Parkinson's disease and tau neurofibrillary tangles in Alzheimer's disease. These aggregates impair mitochondrial function, while dysfunctional mitochondria generate reactive oxygen species that further exacerbate proteotoxic stress, creating a pathogenic cycle. This highlights the functional interplay between mitochondria and the UPS. Recent studies have uncovered phosphorylation of ubiquitin at serine 65 by the mitochondrial kinase PINK1 as a key signal of mitochondrial dysfunction. Phospho-Ser65-ubiquitin (pUb) has emerged as an indicator of mitochondrial health and a potential biomarker for aging and neurodegenerative disease. However, due largely to a lack of tools, little is known about the role of pUb in cellular physiology. Here, we review the current landscape of pUb biology, the phospho-ubiquitome, and its role as biomarker for mitochondrial health and neurodegeneration.