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Distinct associations of peripheral mtDNA copy number and bioenergetic function with cognition in women with HIV and psychiatric comorbidities
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AIDS August 06, 2026
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Discussion
This study provides evidence that distinct peripheral mitochondrial markers are differentially associated with cognitive performance in virally suppressed WWH with cognitive impairment. Whereas mtDNAcn showed only modest and domain-specific associations with cognition, mitochondrial bioenergetic function demonstrated strong relationships with both verbal and working memory performance. Specifically, increased mitochondrial proton leak was associated with poorer verbal recall, verbal recognition, and working memory. In addition, higher mtDNAcn was associated with reduced maximum respiration and spare respiratory capacity, suggesting a complex relationship between mitochondrial content and functional capacity in WWH.
Mitochondrial proton leak emerged as the mitochondrial marker most strongly associated with memory performance, suggesting that markers of mitochondrial dysfunction rather than mitochondrial abundance alone may be more closely related to cognitive outcomes in this population. These results provide initial evidence linking peripheral mitochondrial dysfunction with memory performance in WWH and highlight mitochondrial bioenergetic pathways as an important area for future investigation.
Background:
Women with HIV (WWH) are disproportionately affected by cognitive impairment across multiple domains, with learning and memory consistently among the most vulnerable. Mechanistic investigations into the increased burden of cognitive impairment in people with HIV have highlighted mitochondrial dysfunction as a potential contributor. This study examined associations between two peripheral markers of mitochondrial health, mitochondrial DNA copy number (mtDNAcn) and mitochondrial bioenergetic function, and cognitive function in WWH. We hypothesized that mtDNAcn and mitochondrial function metrics would demonstrate distinct associations with cognitive outcomes, particularly learning and memory.
Methods:
Fifty-eight WWH completed 12 neuropsychological tests assessing - verbal learning, verbal memory (recall and recognition), attention, working memory, executive function, fluency, processing speed, and motor function. Peripheral blood mononuclear cells (PBMCs) were isolated, and mitochondrial health was assessed using qPCR (mtDNAcn) and the Seahorse Cell Mito Stress Test (mitochondrial function). Pearson correlations examined associations between mitochondrial health and cognitive domain scores.
Results:
Participants were on average 54.9 years old (SD = 8.2), 94.8% were Black, 58.6% had a lifetime diagnosis of major depressive disorder, and 63.7% met criteria for cognitive impairment in ≥2 domains. 34.4% met criteria for lifetime posttraumatic stress disorder. Cognitive impairment in two domains was present in 63.7% of participants.
Higher mitochondrial proton leak was significantly associated with worse verbal memory including recall (r = -0.396, P = 0.002) and recognition (r = -0284, P = 0.031), as well as poorer working memory (r = -0.261, P = 0.048). No significant associations were observed between mtDNAcn and cognition.
Conclusions:
These findings identify peripheral mitochondrial proton leak as a potential biological correlate of verbal and working memory difficulties in WWH and highlight the importance of assessing multiple dimensions of mitochondrial health when investigating cognitive impairment.
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