The unexplored Nexus: Mitochondria derived microproteins and Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and mainly occurs in people above the age of 60 years. It is defined by the progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta, which results in the classic motor symptoms. Though aggregation of alpha-synuclein and Lewy body formation are still the core of the disease pathogenesis, PD pathogenesis is complex with mitochondrial dysfunction, oxidative stress, neuroinflammation, impaired autophagy, and endoplasmic reticulum (ER)-Golgi stress. Of these, mitochondrial dysfunction has been the focus of special interest because of its key function in energy metabolism and generation of reactive oxygen species (ROS), which can hasten the neuronal damage. Over the past few years, mitochondrial-derived peptides (MDPs), also k/a mitochondrial microproteins such as Humanin, Small Humanin-Like Peptides (SHLPs), and Mitochondrial Open Reading Frame of the 12S rRNA type-c (MOTS-c) have been identified as new hope for modulating cellular stress responses. Their therapeutic opportunities to impact major pathogenic processes in PD, including inflammation, oxidative stress, and metabolic dysfunction, make them new targets for disease-modifying therapies. With the escalating load of PD and the limitation of existing symptomatic therapies, novel molecular targets need to be explored urgently. Research into the mechanisms involving MDPs in PD not only enhances the insight into disease mechanisms but could potentially lead the way toward next-generation therapies. This article is intended to thoroughly review the role of MDPs in PD pathogenesis and highlight their importance as novel therapeutic agents. With the growing burden of PD and the absence of disease-modifying therapies, exploring novel mitochondrial signaling pathways offers an urgently needed therapeutic direction.