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Human studies of mitochondrial biology demonstrate an overall lack of binary sex differences: A multivariate meta-analysis.

ABSTRACT: Mitochondria are maternally inherited organelles that play critical tissue-specific roles, including hormone synthesis and energy production, that influence human development, health, and aging. However, whether mitochondria from women and men exhibit consistent biological differences remains unclear, representing a major gap in knowledge. This meta-analysis systematically examined four domains and six subdomains of mitochondrial biology (total 39 measures), including mitochondrial content, respiratory capacity, reactive oxygen species (ROS) production, morphometry, and mitochondrial DNA copy number. Standardized effect sizes (Hedge's g) of sex differences were computed for each measure using data in 2258 participants (51.5% women) from 50 studies. Only two measures demonstrated aggregate binary sex differences: higher mitochondrial content in women's WAT and isolated leukocyte subpopulations (g = 0.20, χ² p = .01), and higher ROS production in men's skeletal muscle (g = 0.49, χ² p < .0001). Sex differences showed weak to no correlation with age or BMI. Studies with small sample sizes tended to overestimate effect sizes (r = -.17, p < .001), and sex differences varied by tissue examined. Our findings point to a wide variability of findings in the literature concerning possible binary sex differences in mitochondrial biology. Studies specifically designed to capture sex- and gender-related differences in mitochondrial biology are needed, including detailed considerations of physical activity and sex hormones.

SUBMITTER: Junker A

PROVIDER: S-EPMC9885138 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Human studies of mitochondrial biology demonstrate an overall lack of binary sex differences: A multivariate meta-analysis.

Junker Alex A Wang Jennifer J Gouspillou Gilles G Ehinger Johannes K JK Elmér Eskil E Sjövall Fredrik F Fisher-Wellman Kelsey H KH Neufer P Darrell PD Molina Anthony J A AJA Ferrucci Luigi L Picard Martin M

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20220201 2

Mitochondria are maternally inherited organelles that play critical tissue-specific roles, including hormone synthesis and energy production, that influence human development, health, and aging. However, whether mitochondria from women and men exhibit consistent biological differences remains unclear, representing a major gap in knowledge. This meta-analysis systematically examined four domains and six subdomains of mitochondrial biology (total 39 measures), including mitochondrial content, resp ...[more]

PMID: 35073429

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Project description:BackgroundMyocarditis is an inflammation of the heart muscle most often caused by viral infections. Sex differences in the immune response during myocarditis have been well described but upstream mechanisms in the heart that might influence sex differences in disease are not completely understood.MethodsMale and female BALB/c wild type mice received an intraperitoneal injection of heart-passaged coxsackievirus B3 (CVB3) or vehicle control. Bulk-tissue RNA-sequencing was conducted to better understand sex differences in CVB3 myocarditis. We performed enrichment analysis and functional validation to understand sex differences in the transcriptional landscape of myocarditis and identify factors that might drive sex differences in myocarditis.ResultsAs expected, the hearts of male and female mice with myocarditis were significantly enriched for pathways related to an innate and adaptive immune response compared to uninfected controls. Unique to this study, we found that males were enriched for inflammatory pathways and gene changes that suggested worse mitochondrial electron transport function while females were enriched for pathways related to mitochondrial homeostasis. Mitochondria isolated from the heart of males were confirmed to have worse mitochondrial respiration than females during myocarditis. Unbiased TRANSFAC analysis identified estrogen-related receptor alpha (ERRα) as a transcription factor that may mediate sex differences in mitochondrial function during myocarditis. Transcript and protein levels of ERRα were confirmed as elevated in females with myocarditis compared to males. Differential binding analysis from chromatin immunoprecipitation (ChIP) sequencing confirmed that ERRα bound highly to select predicted respiratory chain genes in females more than males during myocarditis.ConclusionsFemales with viral myocarditis regulate mitochondrial homeostasis by upregulating master regulators of mitochondrial transcription including ERRα.

Dataset Information

Human studies of mitochondrial biology demonstrate an overall lack of binary sex differences: A multivariate meta-analysis.

Publications

Human studies of mitochondrial biology demonstrate an overall lack of binary sex differences: A multivariate meta-analysis.

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