Sex-associated differences in mitochondrial function in human peripheral blood mononuclear cells (PBMCs) and brain

Area of Science:

• Neuroscience and Aging Research
• Mitochondrial Biology and Metabolism
• Sex Differences in Human Physiology

Background:

• Alzheimer's disease (AD), a prevalent dementia, disproportionately affects women.
• Mitochondrial dysfunction (MD) is a key factor in AD pathogenesis and can be detected early in peripheral tissues.
• The relationship between peripheral mitochondrial function, cerebral energy metabolism, and sex-specific differences remains unclear.

Purpose of the Study:

• To investigate the correlation between mitochondrial function in peripheral mononuclear blood cells (PBMCs) and brain energy metabolites.
• To examine sex-specific differences in mitochondrial function and energy metabolism in healthy individuals.
• To determine if PBMCs can serve as a surrogate marker for cerebral mitochondrial function.

Main Methods:

• Pilot study involving 9 males and 15 females (mean age 30.8 years).
• Measurement of mitochondrial respiration, respiratory complex activity, and adenosine triphosphate (ATP) levels in isolated PBMCs.
• Quantification of brain energy metabolites using 1H-magnetic resonance spectroscopy (MRS).

Main Results:

• Females showed significantly higher mitochondrial complex activity (I, I+II, IV), uncoupled respiration, and electron transport system (ETS) capacity in PBMCs compared to males.
• Female participants had approximately 10% higher ATP levels and significantly higher citrate synthase (CS) activity in PBMCs.
• Higher N-acetylaspartate (NAA) concentrations were observed in female brains (white and gray matter), indicating sex-associated differences in both peripheral and central energy metabolism, though no direct correlation was found between PBMC and brain parameters.

Conclusions:

• Significant sex-associated differences in mitochondrial function exist in healthy individuals, evident in both PBMCs and the brain.
• PBMCs represent a feasible surrogate marker for assessing human mitochondrial function and energy metabolism differences.
• The findings highlight the critical need for sex-specific considerations in therapies targeting mitochondrial dysfunction.