Mitochondrial Function and Parkinson’s Disease: From the Perspective of the Electron Transport Chain

Abstract

Parkinson’s disease (PD) is known as a mitochondrial disease. Some even regarded it specifically as a disorder of the complex I of the electron transport chain (ETC). The ETC is fundamental for mitochondrial energy production which is essential for neuronal health. In the past two decades, more than 20 PD-associated genes have been identified. Some are directly involved in mitochondrial functions, such as PRKN, PINK1, and DJ-1. While other PD-associate genes, such as LRRK2, SNCA, and GBA1, regulate lysosomal functions, lipid metabolism, or protein aggregation, some have been shown to indirectly affect the electron transport chain. The recent identification of CHCHD2 and UQCRC1 that are critical for functions of complex IV and complex III, respectively, provide direct evidence that PD is more than just a complex I disorder. Like UQCRC1 in preventing cytochrome c from release, functions of ETC proteins beyond oxidative phosphorylation might also contribute to the pathogenesis of PD.

Astrocytes in Neurodegeneration: Inspiration From Genetics

“…Mitophagy is mediated by these genes via the PINK1/parkin pathway. PINK1 protein is a mitochondrial kinase, parkin is an E3 ubiquitin ligase, and DJ-1 protein participate in proteasome degradation (Panicker et al, 2017;Li et al, 2021).…”

The Role of Bioenergetics in Neurodegeneration

“…It has been shown that mitochondrial dysfunction influences the pathology of PD, especially when considering mitochondrial CI [ 39 , 40 ]. CI is the initial electron acceptor of NADH in the ETC, and the disruption of this complex results in a dramatic loss of energetic capacity.…”

Mitochondrial protein dysfunction in pathogenesis of neurological diseases

“…During electron transfer, three of these complexes (complexes I, III, and IV) pump protons from the matrix to the mitochondrial intermembrane space (IMS), thereby generating an electrochemical proton gradient across the IMM that the F 1 F o -ATP Synthase (also known as ATPase Synthase or complex V) exploits to drive ATP synthesis from adenosine diphosphate (ADP; Breuer et al, 2013 ; Guo R. et al, 2018 ; Signes and Fernandez-Vizarra, 2018 ; Nolfi-Donegan et al, 2020 ). The fundamental role of ETC in mitochondrial energy production is essential for neuronal survival and activity (Li et al, 2021a ). However, both complexes I and III can also transfer single electrons to oxygen, resulting in the formation of oxygen superoxide in the mitochondrial matrix.…”