Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Functional multi-organelle units control inflammatory lipid metabolism of macrophages.

Eukaryotic cells contain several membrane-separated organelles to compartmentalize distinct metabolic reactions. However, it has remained unclear how these organelle systems are coordinated when cells adapt metabolic pathways to support their development, survival or effector functions. Here we present OrgaPlexing, a multi-spectral organelle imaging approach for the comprehensive mapping of six key metabolic organelles and their interactions. We use this analysis on macrophages, immune cells that undergo rapid metabolic switches upon sensing bacterial and inflammatory stimuli. Our results identify lipid droplets (LDs) as primary inflammatory responder organelle, which forms three- and four-way interactions with other organelles. While clusters with endoplasmic reticulum (ER) and mitochondria (mitochondria-ER-LD unit) help supply fatty acids for LD growth, the additional recruitment of peroxisomes (mitochondria-ER-peroxisome-LD unit) supports fatty acid efflux from LDs. Interference with individual components of these units has direct functional consequences for inflammatory lipid mediator synthesis. Together, we show that macrophages form functional multi-organellar units to support metabolic adaptation and provide an experimental strategy to identify organelle-metabolic signalling hubs.

Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling.

Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. Genome-wide association studies of birth weight have highlighted associated variants in more than 200 regions of the genome, but the causal genes are mostly unknown. Rare genetic variants with robust evidence of association are more likely to point to causal genes, but to date, only a few rare variants are known to influence birth weight. We aimed to identify genes that harbour rare variants that impact birth weight when carried by either the fetus or the mother, by analysing whole exome sequence data in UK Biobank participants. We annotated rare (minor allele frequency <0.1%) protein-truncating or high impact missense variants on whole exome sequence data in up to 234,675 participants with data on their own birth weight (fetal variants), and up to 181,883 mothers who reported the birth weight of their first child (maternal variants). Variants within each gene were collapsed to perform gene burden tests and for each associated gene, we compared the observed fetal and maternal effects. We identified 8 genes with evidence of rare fetal variant effects on birth weight, of which 2 also showed maternal effects. One additional gene showed evidence of maternal effects only. We observed 10/11 directionally concordant associations in an independent sample of up to 45,622 individuals (sign test P=0.01). Of the genes identified, IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (all fetal-acting) have known roles in adipose tissue regulation and rare variants in the latter two also showed associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG in both adipocyte differentiation and placental angiogenesis. NOS3, NRK, and ADAMTS8 (fetal and maternal-acting) have been implicated in both placental function and hypertension. Analysis of rare coding variants has identified regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, as well as further evidence for the role of insulin-like growth factors.

Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease.

Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.

Large-scale exome sequence analysis identifies sex- and age-specific determinants of obesity.

Obesity contributes substantially to the global burden of disease and has a significant heritable component. Recent large-scale exome sequencing studies identified several genes in which rare, protein-coding variants have large effects on adult body mass index (BMI). Here we extended such work by performing sex-stratified associations in the UK Biobank study (N∼420,000). We identified genes in which rare heterozygous loss-of-function increases adult BMI in women (DIDO1, PTPRG, and SLC12A5) and in men (SLTM), with effect sizes up to ∼8 kg/m2. This is complemented by analyses implicating rare variants in OBSCN and MADD for recalled childhood adiposity. The known functions of these genes, as well as findings of common variant genome-wide pathway enrichment analyses, suggest a role for neuron death, apoptosis, and DNA damage response mechanisms in the susceptibility to obesity across the life-course. These findings highlight the importance of considering sex-specific and life-course effects in the genetic regulation of obesity.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83, which we demonstrate amplifies signaling of MC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Rare variants in the MECP2 gene in girls with central precocious puberty: a translational cohort study.

BACKGROUND: Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype. METHODS: In this translational cohort study, participants were recruited from seven tertiary centres from five countries (Brazil, Spain, France, the USA, and the UK). Patients with idiopathic central precocious puberty were investigated for rare potentially damaging variants in the MECP2 gene, to assess whether MECP2 might contribute to the cause of central precocious puberty. Inclusion criteria were the development of progressive pubertal signs (Tanner stage 2) before the age of 8 years in girls and 9 years in boys and basal or GnRH-stimulated LH pubertal concentrations. Exclusion criteria were the diagnosis of peripheral precocious puberty and the presence of any recognised cause of central precocious puberty (CNS lesions, known monogenic causes, genetic syndromes, or early exposure to sex steroids). All patients included were followed up at the outpatient clinics of participating academic centres. We used high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in an additional 271 patients. Hypothalamic expression of Mecp2 and colocalisation with GnRH neurons were determined in mice to show expression of Mecp2 in key nuclei related to pubertal timing regulation. FINDINGS: Between Jun 15, 2020, and Jun 15, 2022, 404 patients with idiopathic central precocious puberty (383 [95%] girls and 21 [5%] boys; 261 [65%] sporadic cases and 143 [35%] familial cases from 134 unrelated families) were enrolled and assessed. We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (Arg97Cys) in two monozygotic twin sisters with central precocious puberty and microcephaly; a de novo missense variant (Ser176Arg) in one girl with sporadic central precocious puberty, obesity, and autism; and an insertion (Ala6_Ala8dup) in two unrelated girls with sporadic central precocious puberty. Additionally, we identified one rare heterozygous 3'UTR MECP2 insertion (36_37insT) in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Mecp2 protein colocalised with GnRH expression in hypothalamic nuclei responsible for GnRH regulation in mice. INTERPRETATION: We identified rare MECP2 variants in girls with central precocious puberty, with or without mild neurodevelopmental abnormalities. MECP2 might have a role in the hypothalamic control of human pubertal timing, adding to the evidence of involvement of epigenetic and genetic mechanisms in this crucial biological process. FUNDING: Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and the Wellcome Trust.

Characterization of dominant-negative growth hormone receptor variants reveals a potential therapeutic target for short stature.

OBJECTIVE: Growth hormone insensitivity (GHI) encompasses growth restriction, normal/elevated growth hormone (GH), and low insulin-like growth factor I (IGF1). "Nonclassical" GHI is poorly characterized and is rarely caused by heterozygous dominant-negative (DN) variants located in the intracellular or transmembrane domains of the GH receptor (GHR). We sought to determine the molecular mechanisms underpinning the growth restriction in 2 GHI cases. METHODS AND DESIGN: A custom-made genetic investigative pipeline was exploited to identify the genetic cause of growth restriction in patients with GHI. Nanoluc binary technology (NanoBiT), in vitro splicing assays, western blotting, and flow cytometry, characterized the novel GHR variants. RESULTS: Novel heterozygous GHR variants were identified in 2 unrelated patients with GHI. In vitro splicing assays indicated both variants activated the same alternative splice acceptor site resulting in aberrant splicing and exclusion of 26 base pairs of GHR exon 9. The GHR variants produced truncated receptors and impaired GH-induced GHR signaling. NanoBiT complementation and flow cytometry showed increased cell surface expression of variant GHR homo/heterodimers compared to wild-type (WT) homodimers and increased recombinant human GH binding to variant GHR homo/heterodimers and GH binding protein (GHBP) cleaved from the variant GHRs. The findings demonstrated increased variant GHR dimers and GHBP with resultant GH sequestration. CONCLUSION: We identified and characterized 2 novel, naturally occurring truncated GHR gene variants. Intriguingly, these DN GHR variants act via the same cryptic splice acceptor site, highlighting impairing GH binding to excess GHBP as a potential therapeutic approach.

RNAi-mediated knockdown of two orphan G protein-coupled receptors reduces fecundity in the yellow fever mosquito Aedes aegypti.

G protein-coupled receptors (GPCRs) control numerous physiological processes in insects, including reproduction. While many GPCRs have known ligands, orphan GPCRs do not have identified ligands in which they bind. Advances in genomic sequencing and phylogenetics provide the ability to compare orphan receptor protein sequences to sequences of characterized GPCRs, and thus gain a better understanding of the potential functions of orphan GPCRs. Our study sought to investigate the functions of two orphan GPCRs, AAEL003647 and AAEL019988, in the yellow fever mosquito, Aedes aegypti. From our phylogenetic investigation, we found that AAEL003647 is orthologous to the SIFamide-2/SMYamide receptor. We also found that AAEL019988 is orthologous to the Trapped in endoderm (Tre1) receptor of Drosophila melanogaster. Next, we conducted a tissue-specific expression analysis and found that both receptors had highest expression in the ovaries, suggesting they may be important for reproduction. We then used RNA interference (RNAi) to knock down both genes and found a significant reduction in the number of eggs laid per individual female mosquito, suggesting both receptors are important for Ae. aegypti reproduction.

Communicating with health providers and romantic partners: The impact of negative emotions on quality of life for individuals with hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic, inflammatory, debilitating skin disease that impacts an estimated 1 to 4% of the population; women are twice as likely to be diagnosed as men. There is no cure for HS, and many patients face a lifetime of various healthcare appointments, medical interventions, and personal experiences living with the disease. Objective: This study aimed to explore social, emotional, and medical experiences for individuals with HS, and to understand connections between those experiences and quality of life. Methods: Participants (n = 243) in the community-based convenience sample completed a cross-sectional survey about their experiences and quality of life and reported high rates of anxiety, embarrassment, and depressed mood. These and other negative emotions were commonly experienced during interactions with healthcare providers and romantic partners. Results: Participants who had more negative interactions with providers and partners surrounding their HS tended to experience a lower quality of life. Limitations: Limited generalizability due to convenience sampling. Conclusion: Providers should consider how patients experience patient -provider communication about HS, and how this communication impacts other areas of patients' lives, including quality of life, mental health, and romantic relationships. Future care approaches should prioritize mental health strategies in HS patients' care plans, and establish partnerships between dermatology practices and mental health professionals to aid in the multidisciplinary approach recommended for the treatment of HS.

The value of process evaluation for public health interventions: field-case studies for non-communicable disease prevention and management in five countries.

Complex interventions are needed to effectively tackle non-communicable diseases. However, complex interventions can contain a mix of effective and ineffective actions. Process evaluation (PE) in public health research is of great value as it could clarify the mechanisms and contextual factors associ-ated with variation in the outcomes, better identify effective components, and inform adaptation of the intervention. The aim of this paper is to demonstrate the value of PE through five case studies that span the research cycle. The interven-tions include using digital health, salt reduction strategies, use of fixed dose combinations, and task shifting. Insights of the methods used, and the implications of the PE findings to the project, were discussed. PE of complex interventions can refute or confirm the hypothesized mechanisms of action, thereby enabling intervention refinement, and identifying implementation strategies that can address local contextual needs, so as to improve service delivery and public health outcomes.

A Qualitative Analysis to Understand Perception about Medication-Related Problems among Older Minority Adults in a Historically Black Community.

Older adults taking multiple chronic medications experience an increased risk of adverse drug events and other medication-related problems (MRP). Most current literature on medication management involves researcher-driven intervention, yet few studies investigate patients' understanding of MRP in a diverse community setting. This report investigates patients' perception of MRP and patient-centered strategies among a cohort of the older adult group in a historically Black urban community. The study design is qualitative using structured open-ended questions in a multidisciplinary patient-centered focus group. Patients (age 65 years or older) taking seven or more medications were recruited. The group comprises patients, caregivers, pharmacists, health educators, a physician, and a nurse. Recordings of the group discussion are transcribed verbatim and analyzed using thematic content analysis and categorized by codes developed from the social-ecological model. The group reports patient-provider relationships, previous experience, fear of side effects played important roles in medication adherence. There is an unmet need for medication management education and tools to organize complex medication lists from multiple providers. This study provides important insights into MRP experienced by minority older adults and provided researchers with potential strategies for future interventions.

Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells.

Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-ß on their surface and LAPHi MCs that stimulate Foxp3+ Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-ß inhibits the tolerogenic ability of LAPHi MCs. Furthermore, adoptive transfer of LAPHi MCs promotes Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAPHi MCs, slows cancer progression. Single-cell RNA-Seq analysis on tumor-derived immune cells revealed LAPHi dominated cell subsets with distinct immunosuppressive signatures, including those with high levels of MHCII and PD-L1 genes. Analogous to mice, LAP is expressed on myeloid suppressor cells in humans, and these cells are increased in glioma patients. Thus, our results identify a previously unknown function by which LAPHi MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer.

Effect of a Digital Intervention on Depressive Symptoms in Patients With Comorbid Hypertension or Diabetes in Brazil and Peru: Two Randomized Clinical Trials.

Importance: Depression is a leading contributor to disease burden globally. Digital mental health interventions can address the treatment gap in low- and middle-income countries, but the effectiveness in these countries is unknown. Objective: To investigate the effectiveness of a digital intervention in reducing depressive symptoms among people with diabetes and/or hypertension. Design, Setting, and Participants: Participants with clinically significant depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] score ≥10) who were being treated for hypertension and/or diabetes were enrolled in a cluster randomized clinical trial (RCT) at 20 sites in São Paulo, Brazil (N=880; from September 2016 to September 2017; final follow-up, April 2018), and in an individual-level RCT at 7 sites in Lima, Peru (N=432; from January 2017 to September 2017; final follow-up, March 2018). Interventions: An 18-session, low-intensity, digital intervention was delivered over 6 weeks via a provided smartphone, based on behavioral activation principles, and supported by nurse assistants (n = 440 participants in 10 clusters in São Paulo; n = 217 participants in Lima) vs enhanced usual care (n = 440 participants in 10 clusters in São Paulo; n = 215 participants in Lima). Main Outcomes and Measures: The primary outcome was a reduction of at least 50% from baseline in PHQ-9 scores (range, 0-27; higher score indicates more severe depression) at 3 months. Secondary outcomes included a reduction of at least 50% from baseline PHQ-9 scores at 6 months. Results: Among 880 patients cluster randomized in Brazil (mean age, 56.0 years; 761 [86.5%] women) and 432 patients individually randomized in Peru (mean age, 59.7 years; 352 [81.5%] women), 807 (91.7%) in Brazil and 426 (98.6%) in Peru completed at least 1 follow-up assessment. The proportion of participants in São Paulo with a reduction in PHQ-9 score of at least 50% at 3-month follow-up was 40.7% (159/391 participants) in the digital intervention group vs 28.6% (114/399 participants) in the enhanced usual care group (difference, 12.1 percentage points [95% CI, 5.5 to 18.7]; adjusted odds ratio [OR], 1.6 [95% CI, 1.2 to 2.2]; P = .001). In Lima, the proportion of participants with a reduction in PHQ-9 score of at least 50% at 3-month follow-up was 52.7% (108/205 participants) in the digital intervention group vs 34.1% (70/205 participants) in the enhanced usual care group (difference, 18.6 percentage points [95% CI, 9.1 to 28.0]; adjusted OR, 2.1 [95% CI, 1.4 to 3.2]; P < .001). At 6-month follow-up, differences across groups were no longer statistically significant. Conclusions and Relevance: In 2 RCTs of patients with hypertension or diabetes and depressive symptoms in Brazil and Peru, a digital intervention delivered over a 6-week period significantly improved depressive symptoms at 3 months when compared with enhanced usual care. However, the magnitude of the effect was small in the trial from Brazil and the effects were not sustained at 6 months. Trial Registration: ClinicalTrials.gov: NCT02846662 (São Paulo) and NCT03026426 (Lima).

Building Community-Engaged Multidisciplinary Partnerships to Improve Medication Management in Elderly Patients With Multiple Chronic Conditions.

PURPOSE: Many studies in preventing adverse drug events have been researcher-driven, yet few have engaged patients in the development of a project. This project aims to engage minority elderly patients with multiple chronic conditions in the development of research questions and strategies to improve medication safety. METHODS: Elderly patients (≥65 years old) who were prescribed 7 or more chronic medications were recruited through a university-based aging resource network in a historically African American community in Houston, Texas. Patients and a caregiver participated in a multidisciplinary workgroup comprised of a physician, pharmacists, a nurse, health educators, and a social worker. Patients were engaged by utilizing the 4 patient-centered outcomes research engagement principles. The workgroup created a strategic plan, completed an environmental scan, identified research problems, and reviewed current evidence-based approaches in the literature. Workgroup findings were presented to a broader audience within a community town hall setting, and input was collected from a community-wide survey. RESULTS: From April 2018 to July 2018, 3 patients and 1 caregiver participated in 5 multidisciplinary workgroup meetings. A total of 74 seniors attended the town hall meeting, and 69 completed the surveys. The most common drug-related problems among survey participants were doubts about drug advertisements (79%) and drug interactions (70%). Most participants (88%) were more comfortable in receiving face-to-face counseling compared to an app or virtual visits. Findings aided in developing 3 grant proposals. CONCLUSIONS: This narrative provides a roadmap for conducting multidisciplinary, patient-centered participatory research to refine research strategies in minimizing drug-related problems.

"It makes it more real": Examining ambiguous fetal meanings in abortion care.

The role of fetal development in abortion work is unresolved, mirroring a broader cultural ambivalence regarding the fetus. The collective, cultural notion of fetuses tends to lie on a dichotomy between "clump of cells" and "baby," with little public attention to the realities of fetal development during all stages of pregnancy. This tension is exacerbated by an absence of medically accurate images of aborted fetal tissue available to lay audiences. In this paper, we examine how independent abortion providers manage contradictory messages surrounding the fetus when providing patient-centered pregnancy tissue viewing (PCV). More specifically, we investigate how providers navigate public and private understandings of the fetus in their healthcare provision amidst a void of nuanced fetal imagery. Through interviews with 25 independent abortion providers in the United States, we analyze the discursive framings providers employ to make sense of the fetus and provision of PCV. Using a symbolic interactionism framework, we grouped results into three overarching themes: tensions in language, the impact of gestation as de- or re-stigmatizing, and looking as "making it more real." Our findings support the notion that the fetus is largely socially constructed, mutable, and variant across individuals, context, and time; our findings also highlight abortion providers' ability to hold nuanced and sometimes conflicting thoughts and feelings about fetuses while providing patient-centered care. This study addresses a largely overlooked practice within medical sociology and furthers our understanding of how cultural narratives shape the provision and meanings of patient-centered care, the professional socialization of healthcare workers, and the patient-provider interaction.

The option to look: patient-centred pregnancy tissue viewing at independent abortion clinics in the United States.

Abortion providers' approaches to patient-centred pregnancy tissue viewing (PCV) - when a patient requests to see their products of conception - is understudied in abortion care. This mixed-method study aimed to identify: (1) if, when, and how PCV is facilitated at US independent abortion clinics; (2) how staff are trained to offer viewing; and (3) provider experiences facilitating PCV. We surveyed administrators from 22 independent abortion clinics affiliated with the Abortion Care Network about their PCV practices and then completed in-depth semi-structured interviews with 25 providers to better understand their experiences facilitating PCV. Results indicate that most of the clinics that provide PCV do so by patient request. A variety of providers facilitate viewing, including counsellors, educators, physicians, nurses, and medical assistants. Timing, viewing location, and staff training vary by facility. Benefits of and barriers to PCV emerged through three themes: (1) patient-centred care; (2) misinformation about fetal tissue; and (3) personal navigations as providers. Providers and administrators report PCV aligns with their patient-centred clinic missions and offers patients opportunities for choice, closure, and access to information. Yet, anti-abortion misinformation about fetal tissue impacts the ways providers must navigate complex conversations about PCV professionally and personally. Clinic resources and concern about adverse patient reactions to identifiable fetal parts present barriers to offering viewing. Understanding providers' experiences and approaches to PCV is an important first step to developing quality practices that can be shared across clinics. The findings of this study support the need for more research and training on PCV in abortion care.

Mitoprotective therapy prevents rapid, strain-dependent mitochondrial dysfunction after articular cartilage injury.

Posttraumatic osteoarthritis (PTOA) involves the mechanical and biological deterioration of articular cartilage that occurs following joint injury. PTOA is a growing problem in health care due to the lack of effective therapies combined with an aging population with high activity levels. Recently, acute mitochondrial dysfunction and altered cellular respiration have been associated with cartilage degeneration after injury. This finding is particularly important because recently developed mitoprotective drugs, including SS peptides, can preserve mitochondrial structure and function after acute injury in other tissues. It is not known, however, if cartilage injury induces rapid structural changes in mitochondria, to what degree mitochondrial dysfunction in cartilage depends on the mechanics of injury or the time frame over which such dysfunction develops. Similarly, it is unknown if SS-peptide treatment can preserve mitochondrial structure and function after cartilage injury. Here, we combined fast camera elastography, longitudinal fluorescence assays, and computer vision techniques to track the fates of thousands of individual cells. Our results show that impact induces mechanically dependent mitochondrial depolarization within a few minutes after injury. Electron microscopy revealed that impact causes rapid structural changes in mitochondria that are related to reduced mitochondrial function, namely, fission and loss of cristae structure. We found that SS-peptide treatment prior to impact protects the mitochondrial structure and preserves mitochondrial function at levels comparable with that of unimpacted control samples. Overall, this study reveals the vital role of mitochondria in mediating cartilage's peracute (within minutes) response to traumatic injury and demonstrates mitoprotection as a promising therapeutic strategy for injury-induced cartilage damage.