Connecting the dots between mitochondrial dysfunction and Parkinson's disorder: focus mitochondria-targeting therapeutic paradigm in mitigating the disease severity

Abstract

Mitochondria are unique cell organelles, which exhibit multifactorial roles in numerous cell physiological processes, significantly preserving the integrity of neural synaptic interconnections, mediating ATP production, and regulating apoptotic signaling pathways and calcium homeostasis. Multiple neurological disorders occur as a consequence of impaired mitochondrial functioning, with greater sensitivity of dopaminergic (DA) neurons to mitochondrial dysfunction, due to oxidative nature and low mitochondrial mass, thus supporting the contribution of mitochondrial impairment in Parkinson's disorder (neuronal damage due to curbed dopamine levels). The pathophysiology of the second most common disorder, PD, is potentiated by various mitochondrial homeostasis regulating genes, as discussed in the review. The PD symptoms are known to be aggravated by multiple mitochondria-linked alterations, like reactive oxygen species (ROS) production, Ca2+ buffering, imbalanced mitochondrial dynamics (fission, fusion, mitophagy), biogenetic dysfunctions, disrupted mitochondrial membrane potential (MMP), protein aggregation, neurotoxins, and genetic mutations, which manifest the central involvement of unhealthy mitochondria in neurodegeneration, resulting in retarded DA neurons in region of substantia nigra pars compacta (SNpc), causing PD. Furthermore, the review tends to target altered mitochondrial components, like oxidative stress, inflammation, biogenetic alterations, impaired dynamics, uncontrolled homeostasis, and genetic mutations, to provide a sustainable and reliable alternative in PD therapeutics and to overcome the pitfalls of conventional therapeutic agents. Therefore, the authors elaborate the relationship between PD pathogenesis and mitochondrial dysfunctions, followed by a suitable mitochondria-targeting therapeutic portfolio, as well as future considerations, aiding the researchers to investigate novel strategies to mitigate the severity of the disease.

Keywords: Apoptotic signaling; Calcium homeostasis; Mitochondria; Neurodegeneration; Neurotoxins; Parkinson’s disorder.