mtDNA Maintenance and Alterations in the Pathogenesis of Neurodegenerative Diseases

Abstract

Considerable evidence indicates that the semiautonomous organelles mitochondria play key roles in the progression of many neurodegenerative disorders. Mitochondrial DNA (mtDNA) encodes components of the OXPHOS complex but mutated mtDNA accumulates in cells with aging, which mirrors the increased prevalence of neurodegenerative diseases. This accumulation stems not only from the misreplication of mtDNA and the highly oxidative environment but also from defective mitophagy after fission. In this review, we focus on several pivotal mitochondrial proteins related to mtDNA maintenance (such as ATAD3A and TFAM), mtDNA alterations including mtDNA mutations, mtDNA elimination, and mtDNA release-activated inflammation to understand the crucial role played by mtDNA in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Our work outlines novel therapeutic strategies for targeting mtDNA.

Keywords: Alzheimer’s disease; Huntington’s disease; Mitochondrial DNA (mtDNA); Parkinson’s disease; amyotrophic lateral sclerosis; mitophagy; reactive oxygen species (ROS).

Fig. (1)

mtDNA maintenance and alteration. The proteins related to mtDNA maintenance (e.g., TFAM, POLG, Twinkle, OPA1) are encoded by nDNA and contribute to mtDNA maintenance by participating in nucleoid formation, mtDNA replication, and mitochondrial dynamics. Impaired mitochondrial maintenance results in point mutations, deletion, or even depletion of the mitochondrial genome. Another cause of mtDNA mutations is oxidative stress triggered by ROS generated by electron leakage from complexes I and III. mtDNA mutations and deletions stimulate the production of new ROS, creating a vicious cycle. Damaged mtDNA accumulates in the mitochondria and causes clinical symptoms when the mutational load exceeds a threshold. In the meantime, damaged mitochondria can be rescued by fusion with other mitochondria or by fission and mitophagy. When the damage exceeds the mitochondrial quality control, the mPTP will remain open and the mtDNA breaks and is extruded into the cytoplasm, while nucleoids are extruded with the activation of Bax/Bak. These nucleoids and mtDNA fragments can further be extruded into the extracellular space via MVBs (multivesicular bodies) recognized by DNA-binding receptors within cGAS and TLR-9, ultimately triggering inflammation.