Coenzyme Q10 Supplementation in Aging and Disease.

Mitochondrial diseases are a group of genetic disorders that are characterized by defects in oxidative phosphorylation and caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode structural mitochondrial proteins or proteins involved in mitochondrial function. Mitochondrial diseases are the most common group of inherited metabolic disorders and are among the most common forms of inherited neurological disorders. One of the challenges of mitochondrial diseases is the marked clinical variation seen in patients, which can delay diagnosis. However, advances in next-generation sequencing techniques have substantially improved diagnosis, particularly in children. Establishing a genetic diagnosis allows patients with mitochondrial diseases to have reproductive options, but this is more challenging for women with pathogenetic mtDNA mutations that are strictly maternally inherited. Recent advances in in vitro fertilization techniques, including mitochondrial donation, will offer a better reproductive choice for these women in the future. The treatment of patients with mitochondrial diseases remains a challenge, but guidelines are available to manage the complications of disease. Moreover, an increasing number of therapeutic options are being considered, and with the development of large cohorts of patients and biomarkers, several clinical trials are in progress.

The textbook description of mitochondrial respiratory complexes (RCs) views them as free-moving entities linked by the mobile carriers coenzyme Q (CoQ) and cytochrome c (cyt c). This model (known as the fluid model) is challenged by the proposal that all RCs except complex II can associate in supercomplexes (SCs). The proposed SCs are the respirasome (complexes I, III, and IV), complexes I and III, and complexes III and IV. The role of SCs is unclear, and their existence is debated. By genetic modulation of interactions between complexes I and III and III and IV, we show that these associations define dedicated CoQ and cyt c pools and that SC assembly is dynamic and organizes electron flux to optimize the use of available substrates.

Parkinson's disease (PD) is the second most common neurodegenerative disease. About 2% of the population above the age of 60 is affected by the disease. The pathological hallmarks of the disease include the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies that are made of α-synuclein. Several theories have been suggested for the pathogenesis of PD, of which mitochondrial dysfunction plays a pivotal role in both sporadic and familial forms of the disease. Dysfunction of the mitochondria that is caused by bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations linked to mitochondria, and changes in dynamics of the mitochondria such fusion or fission, changes in size and morphology, alterations in trafficking or transport, altered movement of mitochondria, impairment of transcription, and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we provide a detailed overview of the mechanisms that can cause mitochondrial dysfunction in PD. We bring to the forefront, new signaling pathways such as the retromer-trafficking pathway and its implication in the disease and also provide a brief overview of therapeutic strategies to improve mitochondrial defects in PD. Bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations, alterations in mitochondrial dynamics, alterations in trafficking/transport and mitochondrial movement, abnormal size and morphology, impairment of transcription and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we focus on the mechanisms underlying mitochondrial dysfunction in PD and bring to the forefront new signaling pathways that may be involved in PD. We also provide an overview of therapeutic strategies to improve mitochondrial defects in PD. This article is part of a special issue on Parkinson disease.