Joyonna Gamble-George

Male infertility is recognized as a complex condition associated with aging, yet its association with mitochondrial structural remodeling is poorly understood. Here, we integrated a multi-model approach to investigate how aging and MICOS complex dysfunction influence male reproductive health. Using the All of Us Research Program, we analyzed 121,064 male participants and performed age stratified PheWAS, LabWAS, and GWAS analyses comparing young (20 to 40 years) and older (≥55 years) cohorts. Male infertility was associated with distinct age dependent clinical phenotypes, laboratory alterations, and candidate loci linked to mitochondrial dysfunction. We examined semen samples using confocal microscopy and transmission electron microscopy upon inhibition of MICOS, which resulted in impaired sperm motility dynamics while increasing oxidative stress. We also used Drosophila melanogaster expressing mitochondrial green fluorescent protein in testes. Older flies displayed significant alterations in spermatid mitochondrial architecture, indicating disruption of mitochondrial network organization through aging. Complementary serial block face scanning electron microscopy and three-dimensional reconstructions of mouse testes revealed extensive age associated mitochondrial remodeling across residual, loose, and germ cell populations. Together, these findings identify mitochondrial MICOS complex integrity as a central regulator of age-associated male infertility across species, highlighting it as potential therapeutic target for age-related reproductive decline.

Background: HIV disproportionately affects cisgender Black women (CBW), yet fewer than 2% of eligible CBW use pre-exposure prophylaxis (PrEP); an effective biomedical HIV prevention method. To improve PrEP uptake, this study identified CBW’s preferences for key features of PrEP delivery programs using a discrete choice experiment (DCE). Methods: CBW were recruited, screened online, and completed a one-time DCE survey. Participants completed 14 choice tasks involving 6 PrEP program attributes: 1) administration method, 2) access location, 3) healthcare integration, 4) provider demographics, 5) payment options, 6) support services. Hierarchical Bayes models estimated attribute importance; latent class analysis was used to group participants by similar preferences. Results: Among 390 participants, administration method was the top-ranked attribute (48%), followed by provider demographics (13.2%), and access location (12%). Preferences clustered into five groups. Group 1 (n=82), younger women with high educational attainment, preferred telehealth initiated bi-monthly injectable PrEP. Group 2 (n=82), older women with lower HIV vulnerability, favored oral and injectable PrEP prescribed by a physician during women’s health visits. Group 3 (n=108) had the highest HIV vulnerability, showed strong interest in PrEP, preferred the vaginal ring accessed through pharmacies or telehealth. Group 4 (n=59) had the lowest access to healthcare, preferred injectable PrEP in clinical settings with income-based cost adjustments. Group 5 (n=59), one of the youngest and economically advantaged, favored the vaginal ring from a pharmacy. Conclusion: Findings indicate administration method, provider type, and access location mattered most to CBW for PrEP programming, indicating the need to use multiprong approaches to bolster PrEP uptake.

Due to aging, the efficiency of kidney function begins to decrease. Dysfunction in mitochondria and their cristae is a hallmark of aging. Therefore, age‐related decline in kidney function could be attributed to changes in mitochondrial ultrastructure, increased reactive oxygen species, and alterations in metabolism and lipid composition. We sought to understand how mitochondrial ultrastructure is altered over time in tubular kidney cells. A serial block face‐scanning electron microscope and manual segmentation using the Amira software were employed to visualize murine kidney samples during the aging process at 3 months (young) and 2 years (old). We found that 2‐year mitochondria are more fragmented with many uniquely shaped mitochondria observed across aging, concomitant with shifts in ROS, metabolomics, and lipid homeostasis. Furthermore, we demonstrate that the mitochondrial contact site and cristae organizing system (MICOS) complex is impaired in the kidney during aging. Disruption of the MICOS complex resulted in altered mitochondrial metabolic function and increased ROS levels. We found significant, detrimental structural changes in the mitochondria of aged kidney tubules, suggesting a potential mechanism underlying the increased frequency of kidney disease with aging. We hypothesize that disruption of the MICOS complex exacerbates mitochondrial dysfunction, creating a vicious cycle of mitochondrial degradation and oxidative stress, which impacts kidney health.

Mitochondrial dysfunction drives hypertensive heart failure and reflects impaired oxidative phosphorylation and altered organelle structure. The mechanisms linking hypertensive signaling to mitochondrial translation and architecture remain unclear. TACO1 is a mitochondrial translational activator required for cytochrome c oxidase subunit I synthesis and may regulate respiratory chain assembly. We tested whether angiotensin II type 1 receptor activation disrupts TACO1-dependent translation and drives inner membrane remodeling. Using mRen also known as (mRen2)27 hypertensive rat hearts, we assessed mitochondrial function, ultrastructure, and metabolism. AT1R activation reduced TACO1-dependent COX I translation and produced a selective deficiency in complex IV activity. This impaired oxidative phosphorylation and increased the production of reactive oxygen species. Mitochondria exhibited reduced volume, increased fragmentation, and disrupted cristae organization with lower integrity scores. Hypertensive hearts also showed reduced expression of OPA1 and MICOS components. Metabolomic profiling separated control and heart failure groups and revealed enrichment of amino acid, nucleotide, and mitochondrial energy pathways. Lipidomic analysis identified coordinated changes across lipid classes consistent with altered membrane composition. Pharmacological AT1R inhibition restored COX I translation, rescued complex IV activity, and improved cristae structure. These findings establish a mechanistic link between hypertensive signaling, mitochondrial translation, cristae organization, and metabolic remodeling in heart failure.

Salt-sensitivity of blood pressure (SSBP) is associated with immune-metabolic dysfunction, yet the mechanism that coordinates sodium exposure, mitochondrial remodeling, and blood pressure response remains undefined. Phenome-wide and laboratory-value association studies (PheWAS and LabWAS) in the All of Us Research Program identified fluid, electrolyte, and acid-base balance disorders and renal phenotypes as the strongest disease associations. At the same time, hypertension was linked to reduced serum potassium, chloride, and eGFR, corroborating the centrality of renal-electrolyte physiology in blood pressure regulation. Using a within-subject sodium challenge in humans, we show that sodium loading reorganizes circulating tricarboxylic acid (TCA) cycle intermediates in proportion to the individual blood pressure response. Transcriptomic profiling of immune cells under high sodium revealed suppression of oxidative phosphorylation, induction of HIF1α-dependent glycolytic gene networks, and rebalancing of the pyruvate dehydrogenase complex. Single-cell chromatin accessibility profiling demonstrated that HIF1α motif activity in circulating immune cells correlates with changes in systolic blood pressure and pulse pressure in salt-sensitive individuals. High sodium induced mitochondrial fragmentation with increased organelle mass and glycolytic capacity. Pharmacological HIF1α inhibition reversed fragmentation while only partially normalizing metabolic output, indicating structural and metabolic remodeling are partially dissociable downstream of HIF1α. Renal HIF1α gain-of-function in mice recapitulated the glycolytic transcriptional response with medullary specificity. Concordantly, Drosophila melanogaster subjected to a high-salt diet exhibited impaired locomotor performance, mitochondrial dysmorphology, intestinal barrier disruption, and cardiac remodeling, establishing evolutionary conservation of sodium-induced end-organ dysfunction independent of an adaptive immune system. Together, these findings identify a HIF1α-dependent axis of mitochondrial metabolic adaptation providing a mechanistic basis for SSBP.

Background: Cisgender Black women (CBW) remain disproportionately affected by HIV in the United States. Condoms, when used consistently and correctly, are an effective and reliable method for reducing acquisition and transmission of HIV and other sexually transmitted infections (STIs). However, consistent condom use among CBW is mixed. This study aimed to garner a contemporary conceptualization of factors impacting condom use among CBW with male sexual partner(s) residing in large urban areas in Texas. Materials and methods: Between December 2020 and January 2022, CBW ( N = 154) were recruited to complete a one-time online survey about HIV prevention and women’s sexual health. Descriptive statistics were used to characterize the study sample by condom use behavior (used condoms/did not use condoms). An inductive qualitative content analysis (IQCA) was used to analyze two open-ended questions about participants reasoning for their condom use or non-use. Results: Condom use during vaginal sex was similarly proportioned (48.7% users; 51.3% non-users), indicating CBW differed in their condom use behaviors. Four themes described contributing factors for condom use (HIV/STI prevention and family planning) and non-use (relational context and intrapersonal factors). Condom use was motivated primarily by perceived HIV/STI and pregnancy prevention, including dual-protection strategies. Condom non-use was driven largely by relational context, such as trust, perceived monogamy, relationship length, and male partners’ preferences, and intrapersonal factors related to pleasure, comfort, or contraceptive reliance. Across both groups, CBW emphasized partner dynamics, communication, and relationship expectations in shaping decisions. Conclusion: The qualitative findings highlight how individual, relational, and intrapersonal factors intersect to influence condom use among CBW.

Background: Among Black women (BW), HIV prevalence is higher among women aged ⩾45 than among those aged N = 83 of N = 390). Hierarchical Bayes model estimated attribute importance; latent class multinomial logit analysis grouped participants by similar preferences. Results: PrEP administration method was the top-ranked attribute (39%), followed by provider demographics (14%) and payment options (13%). Preferences were clustered into three distinct groups. Group 1 ( n = 8) showed higher proportions of worry about acquiring HIV and preferred only a daily pill by a doctor’s office. Group 2 ( n = 35) faced descriptively higher HIV vulnerability and favored injectable PrEP via telehealth supported (in-person) injection delivery from a female provider. Group 3 ( n = 40) had the strongest interest and intention to use PrEP, preferring injectable PrEP from a pharmacist of the same race. Compared to the full sample, aging BW valued PrEP administration, prioritized gender matching alone, and payment options. Conclusion: PrEP program preferences are not uniform among aging BW. Rather than relying on a single PrEP delivery model, programs should be tailored to specific preferences for aging women who consider multiple factors and may need personalized support in PrEP decision-making.

Objective: To identify innovative strategies that may increase recruitment and/or retention of groups less represented in chronic disease clinical research. Methods: A systematic review was conducted. Inclusion criteria were: (a) NIH-defined racial and ethnic minority groups and clinical research; (b) evidence-based, clinical research recruitment and/or retention strategies involving the leading causes of mortality and morbidity in the United States; (c) conducted in the United States; and (d) qualitative design. Data exploring the strategies were extracted and thematically analyzed. Results: Twenty-seven studies were included. Studies focused on cancer (70%), recruitment (93%), and perspectives from clinicians (63%). The most referenced strategies were education (44%), communication (48%), and community-based participatory research (63%). Critical themes include empowerment, transparency, trust, and sustainability. Conclusions: Strategies must prioritize the community and be implemented sustainably, where cultural humility and community-based participatory research are foundational.