Background: Mitochondrial dysfunction has been implicated in the pathogenesis of autoimmune disorders (AIDs), but its causal role in disease susceptibility and progression remains unclear. This study explores potential causal associations between mitochondrial-related genes and AIDs using integrated multi-omics evidence from Mendelian randomization (MR) and colocalization analyses.

Methods: Summary-level datasets from 10 common AIDs (303 590-456 348 participants) and quantitative trait loci (QTL) at the DNA methylation, gene expression, and protein abundance levels (mQTL, eQTL, and pQTL, respectively; 1 980-35 559 participants), as well as mitochondrial DNA copy number (465 809 participants), were analyzed. Instrumental variables were selected from cis-acting variants near 1136 mitochondrial-related genes with strong associations (p_QTL < 5e-08). Summary-data-based MR (SMR) and Bayesian colocalization analyses were applied to identify causal effects, followed by validation assessments integrating multi-omics SMR results.

Results: Four Grade-II mitochondrial genes were causally linked to multiple AIDs. ATAD3A (OR: 1.41; 95% CI: 1.13-1.76, p_SMR = 1.64e-03) and TOP1MT (OR: 1.42; 95% CI: 1.10-1.84, p_SMR = 4.60e-03) were strongly associated with multiple myositis, while SND1 (OR: 1.08; 95% CI: 1.04-1.12, p_SMR = 4.05e-03) was linked to osteoarthritis. Notably, TOP1MT expression conferred protective effects against primary Sjögren's syndrome (OR: 0.57; 95% CI: 0.35-0.95, p_SMR = 8.21e-03). Crucially, only UQCRH was identified with the same variant (rs41292543) exhibiting inverse effects on multiple myositis, including causal effects through cg11235697 methylation (OR: 1.56; 95% CI: 1.23-1.98, p_SMR = 3.02e-04) and protective effects through gene expression (OR: 0.83; 95% CI: 0.72-0.95, p_SMR = 2.78e-04).

Conclusions: These findings provide robust evidence of mitochondrial dysfunction's causal role in AIDs and identify potential pharmacological targets for treatment, offering new insights into precision medicine for AIDs.

Immune nonresponder (INR) HIV-1-infected subjects are characterized by their inability to reconstitute the CD4+ T cell pool after antiretroviral therapy. This is linked to poor clinical outcome. Mechanisms underlying immune reconstitution failure are poorly understood, although, counterintuitively, INRs often have increased frequencies of circulating CD4+ T cells in the cell cycle. While cycling CD4+ T cells from healthy controls and HIV+ patients with restored CD4+ T cell numbers complete cell division in vitro, cycling CD4+ T cells from INRs do not.

Here, we show that cells with the phenotype and transcriptional profile of Tregs were enriched among cycling cells in health and in HIV infection. Yet there were diminished frequencies and numbers of Tregs among cycling CD4+ T cells in INRs, and cycling CD4+ T cells from INR subjects displayed transcriptional profiles associated with the impaired development and maintenance of functional Tregs. Flow cytometric assessment of TGF-β activity confirmed the dysfunction of Tregs in INR subjects. Transcriptional profiling and flow cytometry revealed diminished mitochondrial fitness in Tregs among INRs, and cycling Tregs from INRs had low expression of the mitochondrial biogenesis regulators peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α) and transcription factor A for mitochondria (TFAM). In vitro exposure to IL-15 allowed cells to complete division, restored the expression of PGC1α and TFAM, and regenerated mitochondrial fitness in the cycling Tregs of INRs.

Our data suggest that rescuing mitochondrial function could correct the immune dysfunction characteristic of Tregs in HIV-1-infected subjects who fail to restore CD4+ T cells during antiretroviral therapy.

Background: Mitochondrial dysfunction has frequently been found in HIV-infected patients regardless of whether they received antiretroviral therapy (ART). Accumulating evidence suggests that HIV-infected patients exhibit marked changes in mitochondrial membrane potential (MMP), reactive oxygen species (ROS) accumulation, adenosine triphosphate generation, mitochondrial mass (MM), mitochondrial DNA, etc. However, mitochondrial toxicity in CD4T and CD8T cells caused by different levels of HIV progression and ART is poorly understood.

Methods: Blood samples were obtained from 97 ART-naïve HIV-infected patients with different CD4T cell counts, 97 nucleoside-reverse transcriptase inhibitors-exposed HIV-infected patients, and 25 HIV-negative subjects. MMP, ROS, and MM in CD4T and CD8T cells were assessed by flow cytometry.

Results: In healthy subjects, the levels of MMP and MM in CD4T cells were higher than those in CD8T cells. HIV infection led to an increase in MM in CD4T and CD8T cells, but mainly influenced MMP in CD8T cells and ROS accumulation in CD4T cells. MM in CD4T and CD8T cells gradually increased after the loss of CD4T cells. Although the dynamic changes in MMP in CD4T cells were different from those in CD8T cells during highly active ART, MM in both CD4T and CD8T cells was significantly decreased after 2 years of therapy, but increased again after 3 years.

Conclusions: HIV infection and antiretroviral therapy both led to mitochondrial disturbances in CD4T cells and CD8T cells; however, the abnormal changes in mitochondrial parameters in CD4+T cells were different from those in CD8T cells caused by HIV infection and antiretroviral therapy.

Background: Association of lipoprotein particle size/number and HDL function with mitochondrial oxidative stress and function may underlie the excess cardiovascular (CVD) risk in HIV.

Methods and results: Among HIV infected individuals on stable highly active antiretroviral therapy, we related standard and novel lipid measures [plasma total cholesterol, triglycerides, HDL-C, LDL-C, lipoprotein particle (-P) subclass size and number and HDL function (via cholesterol-efflux capacity)] with oxidative stress [peripheral blood mononuclear cell's mitochondrial-specific 8-oxo-deoxyguanine (8-oxo-dG)] and function markers [oxidative phosphorylation (OXPHOS) NADH dehydrogenase (Complex I) and cytochrome c oxidase (Complex IV) enzyme activities]. Multivariable-adjusted logistic and linear regression analyses were employed adjusting for age, gender, CD4 nadir, viral load, smoking, diabetes, HOMA-IR, hypertension and lipid medications. Among 150 HIV-infected persons (mean age 52 years, 12% women, median CD4 count 524 cell/mm3), low HDL-C and high total cholesterol/HDL-C ratio were related to PBMC 8-oxo-deoxyguanine (p = 0.01 and 0.02 respectively). Large HDL-P and HDL-P size were inversely related to PBMC 8-oxo-deoxyguanine (p = 0.04). Small LDL-P (p = 0.01) and total LDL-P (p = 0.01) were related to decreased OXPHOS Complex I activity. LDL-P was related to decreased OXPHOS Complex IV activity (p = 0.02). Cholesterol efflux capacity was associated with increased OXPHOS Complex IV activity.

Conclusions: HDL concentration and particle size and number are related to decreased PBMC mitochondrial oxidative stress whereas HDL function is positively related to mitochondrial oxidative function. The association we find between atherogenic lipoprotein profile and increased oxidative stress and function suggests these pathways may be important in the pathogenesis of cardiometabolic disease in HIV disease.