Genetic Control over mtDNA and Its Relationship to Major Depressive Disorder

Abstract

SummaryControl over the number of mtDNA molecules per cell appears to be tightly regulated, but the mechanisms involved are largely unknown. Reversible alterations in the amount of mtDNA occur in response to stress suggesting that control over the amount of mtDNA is involved in stress-related diseases including major depressive disorder (MDD). Using low-coverage sequence data from 10,442 Chinese women to compute the normalized numbers of reads mapping to the mitochondrial genome as a proxy for the amount of mtDNA, we identified two loci that contribute to mtDNA levels: one within the TFAM gene on chromosome 10 (rs11006126, p value = 8.73 × 10−28, variance explained = 1.90%) and one over the CDK6 gene on chromosome 7 (rs445, p value = 6.03 × 10−16, variance explained = 0.50%). Both loci replicated in an independent cohort. CDK6 is thus a new molecule involved in the control of mtDNA. We identify increased rates of heteroplasmy in women with MDD, and show from an experimental paradigm using mice that the increase is likely due to stress. Furthermore, at least one heteroplasmic variant is significantly associated with changes in the amount of mtDNA (position 513, p value = 3.27 × 10−9, variance explained = 0.48%) suggesting site-specific heteroplasmy as a possible link between stress and increase in amount of mtDNA. These findings indicate the involvement of mitochondrial genome copy number and sequence in an organism’s response to stress.

The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development

“…Interestingly, alteration in the levels of the mitochondrial protein uncoupling protein 2 (UCP2), which controls substrate oxidation of the mitochondria in neurons (Andrews et al, 2008), as well as mitochondrial fidelity overall, have significant impact on cortical structure and function (Hermes et al, 2016; Kann and Kovacs, 2007; Li et al, 2004; Varela et al, 2016). These findings illustrate that mitochondrial function can facilitate neuropsychiatric disorders, including major depressive disorder (Cai et al, 2015; Converge Consortium, 2015) and intellectual and developmental disability (Ouyang et al, 2016), and substantiate the need for further investigations into similar neurodevelopmental disorders such as ASD.…”

Adverse Childhood Experiences Run Deep: Toxic Early Life Stress, Telomeres, and Mitochondrial DNA Copy Number, the Biological Markers of Cumulative Stress

“…Mitochondria are dynamic cellular organelles that produce energy in the form of adenosine triphosphate, the primary energy currency of the cell. [86] Nevertheless, mtDNAcn and mitochondrial mass change during cell growth and differentiation, physical activity, and oxidative stress. [17] Unlike other organelles, the mitochondrion houses its own genome essential for mitochondrial bioenergetics.…”

Evaluation of mitochondrial DNA copy number estimation techniques

“…Quantitative real-time PCR (qPCR) has been the most widely used method for measuring mtDNA-CN, partly due to its low cost and quick turnaround time. However, recent work has demonstrated the feasibility of accurately measuring mtDNA-CN from preexisting microarray, whole exome sequencing (WES) and whole genome sequencing (WGS) data 2,10, 13 . With these advances, it is important for the field to evaluate these methods in the context of the current gold standard.…”