Precision mitochondrial medicine

Abstract

Mitochondria play a key role in cell homeostasis as a major source of intracellular energy (adenosine triphosphate, ATP), and as metabolic hubs regulating many canonical cell processes. Mitochondrial dysfunction has been widely documented in many common diseases, and genetic studies point towards a causal role in the pathogenesis of specific lateonset disorder. Together this makes targeting mitochondrial genes an attractive strategy for precision medicine. However, the genetics of mitochondrial biogenesis is complex, with over 1100 candidate genes found in two different genomes: the nuclear DNA and mitochondrial DNA (mtDNA). Here we review the current evidence associating mitochondrial genetic variants with distinct clinical phenotypes, with some having clear therapeutic implications. The strongest evidence has emerged through the investigation of rare inherited mitochondrial disorders, but genome-wide association studies also implicate mtDNA variants in the risk of developing common diseases, opening to door for the incorporation of mitochondrial genetic variant analysis in population disease risk stratification.

Introducing Cambridge prisms: Precision medicine

“…The latest developments to be clinically adopted by specialism have been reviewed for the launch of the journal. These articles highlight some of the greatest achievements of precision medicine to date, including within cardiology (Soremekun, 2023 ), neurodegenerative diseases (Tsoi et al, 2023 ), oncology (Chamba, 2023 ; McGough, 2023 ), mitochondrial medicine (Chinnery, 2022 ), and also more recent areas of study including blood type susceptibility from severe disease with COVID-19 (Ellinghaus, 2023 ).…”

Challenges and opportunities to bridge translational to clinical research for personalized mitochondrial medicine

“…PMDs share a defective oxidative phosphorylation (OXPHOS) pathway responsible for mitochondrial ATP synthesis, which predominantly affects organs with high energy demands and a dependence on aerobic metabolism, such as the central and peripheral nervous system (CNS and PNS, respectively), musculosketal system, and cardiac system [ 17 , 18 ]. Thus, patients with a PMD exhibit a wide spectrum of clinical manifestations, including muscle weakness, developmental delays, neurological abnormalities, and metabolic disturbances [ 3 , [19] , [20] , [21] ]. Currently, patients with a progressive and multi-systemic PMD only have access to palliative therapies that fail to halt the progressive decline, resulting in significant disability, morbidity, and premature death [ 22 ].…”

Extracellular vesicle mitochondrial DNA levels are associated with race and mitochondrial DNA haplogroup

“…Mitochondrial dysfunction is linked to aging as well as diseases such as cardiovascular disorders, diabetes mellitus, Parkinson disease, and cancer. 31 , 32 , 33 , 34 Compared with nuclear DNA, mtDNA displays a higher mutation rate, potentially because mtDNA is closer in proximity to reactive oxygen species (ROS). 35 , 36 As mitochondria are maternally inherited without germline recombination, the accumulation of mutations such as single nucleotide polymorphisms (SNPs) in mtDNA can be tracked across human evolutionary history.…”