Is there a special relationship between complex I activity and nigral neuronal loss in Parkinson’s disease? A critical reappraisal

• Published in: Brain research 2021-09, Vol.1767, p.147434-147434, Article 147434
• Main Authors: Subrahmanian, Nitya, LaVoie, Matthew J.
• Format: Article
• Language: English
• Subjects: Mitochondrial complex I; MPTP; NDUFAF2; Parkinson’s disease; PINK1
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2021.147434

•CI toxins, linked to parkinsonism, are useful for generating experimental PD models.•Mitochondrial CI deficit has been observed in tissues from idiopathic PD patients.•Rare genetic mutations affecting mitochondrial proteins are linked to familial PD.•Yet, patients with CI disorders typically fail to manifest unique nigral cell loss.•Whether CI dysfunction drives selective nigral neurodegeneration remains elusive. Parkinson’s disease (PD) is a progressive neurodegenerative disease manifesting both motor and non-motor symptoms. The motor features are generally ascribed to the selective loss of dopamine neurons within the substantia nigra pars compacta. While the precise etiology of PD remains elusive, multiple genetic and environmental elements have emerged as contributing factors. The discovery of MPTP-induced parkinsonism directed intense inquiry towards mitochondrial pathways, with a specific focus on mitochondrial complex I. Consisting of more than 40 subunits, complex I is the first enzyme of the electron transport chain that is required for mitochondrial ATP production. In this review, we present a critical analysis of studies assessing the prevalence and specificity of mitochondrial complex I deficiency in PD. In addition, we take the novel view of incorporating the features of genetically-defined bona fide complex I disorders and the prevalence of nigral involvement in such cases. Through this innovative bi-directional view, we consider both complex I changes in a disease of the substantia nigra and nigral changes in diseases of complex I. We assess the strength of association between nigral cell loss and complex I deficits, as well as the oft under-appreciated heterogeneity of complex I deficiency disorders and the variability of the PD data.