Targeting the Mitochondrial Unfolded Protein Response to Improve Mitochondrial Function
Every cell contains hundreds of mitochondria, generating chemical energy store molecules to power cellular biochemistry. Mitochondrial function declines with age, with evidence indicating that a disruption of quality control mechanisms such as mitophagy is the proximate cause. Underlying that are age-related changes in the expression of proteins involved in mitochondrial dynamics, the fusion and fission of mitochondria. Is it possible to significantly improve mitochondrial function by forcing an upregulation of quality control mechanisms? Approaches such as delivery of NAD+ precursors have yet to reliably improve on the effects of exercise on mitochondrial function, but perhaps more is possible.
The disruption of mitochondrial function is usually caused by the excessive production of reactive oxygen species (ROS), the uncoupling of the mitochondrial electron transport chain (mtETC), or the expression of aberrant or mutated proteins encoded by mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). In addition, mtDNA is more susceptible to mutations due to its proximity to the site of ROS generation and the absence of histone protection. These perturbations are implicated in primary mitochondrial diseases, which are characterized by mutations that affect the nDNA or mtDNA, as well as various age-related diseases, metabolic disorders, heart pathologies, and cancer, which are referred to as secondary mitochondrial diseases.
Mitochondrial homeostasis and proteostasis are essential for the maintenance of mitochondrial function. To this end, mitochondria have renewal mechanisms, such as mitophagy or mitochondrial unfolded protein response (mtUPR), in addition to mitochondrial biogenesis that promotes the growth and formation of new mitochondria. Moreover, other renewal mechanisms have recently emerged, such as mitochondrial-derived vesicles (MDVs). The ability of mitochondria to release their contents into vesicles is a conserved process shared with their bacterial ancestors. When mitochondrial stressors are present, mitochondrial inner and outer membranes become oxidized, leading to their loading into vesicles which are transported to lysosomes or peroxisomes for degradation, removing damaged proteins and thus preventing mitochondrial dysfunction.
All these processes form part of the protein quality control system of the mitochondrion that is vital for mitochondrial function and cell homeostasis. In this review, we focus specifically on mitochondrial biogenesis and the mtUPR and, in particular, on the implication of mtUPR modulation as a potential treatment of primary and secondary mitochondrial diseases. In addition, we discuss the negative consequences of its activation in cancer patients and its overaction in pathological situations.