Genetic Association Study of Common Mitochondrial Variants on Body Fat Mass

Mitochondria play a central role in ATP production and energy metabolism. Previous studies suggest that common variants in mtDNA are associated with several common complex diseases, including obesity. To test the hypothesis that common mtDNA variants influence obesity-related phenotypes, including BMI and body fat mass, we genotyped a total of 445 mtSNPs across the whole mitochondrial genome in a large sample of 2,286 unrelated Caucasian subjects. 72 of these 445 mtSNPs passed quality control criteria, and were used for subsequent analyses. We also classified all subjects into nine common European haplogroups. Association analyses were conducted for both BMI and body fat mass with single mtSNPs and mtDNA haplogroups. Two mtSNPs, mt4823 and mt8873 were detected to be significantly associated with body fat mass, with adjusted P values of 4.94×10-3 and 4.58×10-2, respectively. The minor alleles mt4823 C and mt8873 A were associated with reduced fat mass values and the effect size (β) was estimated to be 3.52 and 3.18, respectively. These two mtSNPs also achieved nominally significant levels for association with BMI. For haplogroup analyses, we found that haplogroup X was strongly associated with both BMI (adjusted P = 8.31×10-3) and body fat mass (adjusted P = 5.67×10-4) Subjects classified as haplogroup X had lower BMI and fat mass values, with the β estimated to be 2.86 and 6.03, respectively. Our findings suggest that common variants in mitochondria might play a role in variations of body fat mass. Further molecular and functional studies will be needed to clarify the potential mechanism

Mitochondrial ATP synthase: architecture, function and pathology

Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F1, situated in the mitochondrial matrix, and Fo, located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. This review covers the architecture, function and assembly of complex V. The role of complex V di-and oligomerization and its relation with mitochondrial morphology is discussed. Finally, pathology related to complex V deficiency and current therapeutic strategies are highlighted. Despite the huge progress in this research field over the past decades, questions remain to be answered regarding the structure of subunits, the function of the rotary nanomotor at a molecular level, and the human complex V assembly process. The elucidation of more nuclear genetic defects will guide physio(patho)logical studies, paving the way for future therapeutic interventions