OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases.

Patients with primary mitochondrial oxidative phosphorylation (OxPhos) defects present with fatigue and multi-system disorders, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. By integrating data from 17 cohorts of patients with mitochondrial diseases (n = 690) we find evidence that these disorders increase resting energy expenditure, a state termed hypermetabolism. We examine this phenomenon longitudinally in patient-derived fibroblasts from multiple donors. Genetically or pharmacologically disrupting OxPhos approximately doubles cellular energy expenditure. This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiency, excluding uncoupling as a general mechanism. Instead, hypermetabolism is associated with mitochondrial DNA instability, activation of the integrated stress response (ISR), and increased extracellular secretion of age-related cytokines and metabokines including GDF15. In parallel, OxPhos defects accelerate telomere erosion and epigenetic aging per cell division, consistent with evidence that excess energy expenditure accelerates biological aging. To explore potential mechanisms for these effects, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations. Taken together, these findings highlight the need to understand how OxPhos defects influence the energetic cost of living, and the link between hypermetabolism and aging in cells and patients with mitochondrial diseases.

Leukocyte cytokine responses in adult patients with mitochondrial DNA defects.

Patients with oxidative phosphorylation (OxPhos) defects causing mitochondrial diseases appear particularly vulnerable to infections. Although OxPhos defects modulate cytokine production in vitro and in animal models, little is known about how circulating leukocytes of patients with inherited mitochondrial DNA (mtDNA) defects respond to acute immune challenges. In a small cohort of healthy controls (n = 21) and patients (n = 12) with either the m.3243A > G mutation or single, large-scale mtDNA deletions, we examined (i) cytokine responses (IL-6, TNF-α, IL-1ß) in response to acute lipopolysaccharide (LPS) exposure and (ii) sensitivity to the immunosuppressive effects of glucocorticoid signaling (dexamethasone) on cytokine production. In dose-response experiments to determine the half-maximal effective LPS concentration (EC50), relative to controls, leukocytes from patients with mtDNA deletions showed 74-79% lower responses for IL-6 and IL-1ß (pIL-6 = 0.031, pIL-1ß = 0.009). Moreover, whole blood from patients with mtDNA deletions (pIL-6 = 0.006), but not patients with the m.3243A > G mutation, showed greater sensitivity to the immunosuppressive effects of dexamethasone. Together, these ex vivo data provide preliminary evidence that some systemic OxPhos defects may compromise immune cytokine responses and increase the sensitivity to immune cytokine suppression by glucocorticoids. Further work in larger cohorts is needed to define the nature of immune dysregulation in patients with mitochondrial disease, and their potential implications for disease phenotypes. KEY MESSAGES: Little is known about leukocyte cytokine responses in patients with mitochondrial diseases. Leukocytes of patients with mtDNA deletions show blunted LPS sensitivity and cytokine responses. Leukocytes of patients with mtDNA deletions are more sensitive to glucocorticoid-mediated IL-6 suppression. Work in larger cohorts is needed to delineate potential immune alterations in mitochondrial diseases.

Social and Non-social Reward Processing and Depressive Symptoms Among Sexual Minority Adolescents.

Sexual minority adolescents (SMA) are more likely to suffer from depression, putatively through experiences of social stress and victimization interfering with processing of social reward. Alterations in neural reward networks, which develop during adolescence, confer risk for the development of depression. Employing both social and monetary reward fMRI tasks, this is the first neuroimaging study to examine function in reward circuitry as a potential mechanism of mental health disparities between SMA and heterosexual adolescents. Eight SMA and 38 heterosexual typically developing adolescents completed self-report measures of depression and victimization, and underwent fMRI during monetary and peer social reward tasks in which they received positive monetary or social feedback, respectively. Compared with heterosexual adolescents, SMA had greater interpersonal depressive symptoms and exhibited blunted neural responses to social, but not monetary, reward in socioaffective processing regions that are associated with depressive symptoms. Specifically, compared with heterosexual adolescents, SMA exhibited decreased activation in the right medial prefrontal cortex, left anterior insula (AI), and right temporoparietal junction (TPJ) in response to being liked. Lower response in the right TPJ was associated with greater interpersonal depressive symptoms. These results suggest that interpersonal difficulties and the underlying substrates of response to social reward (perhaps more so than response to monetary reward) may confer risk for development of depressive symptoms in SMA.

Heightened activity in social reward networks is associated with adolescents' risky sexual behaviors.

Adolescent sexual risk behavior can lead to serious health consequences, yet few investigations have addressed its neurodevelopmental mechanisms. Social neurocircuitry is postulated to underlie the development of risky sexual behavior, and response to social reward may be especially relevant. Typically developing adolescents (N=47; 18M, 29F; 16.3±1.4years; 42.5% sexual intercourse experience) completed a social reward fMRI task and reported their sexual risk behaviors (e.g., lifetime sexual partners) on the Youth Risk Behavior Survey (YRBS). Neural response and functional connectivity to social reward were compared for adolescents with higher- and lower-risk sexual behavior. Adolescents with higher-risk sexual behaviors demonstrated increased activation in the right precuneus and the right temporoparietal junction during receipt of social reward. Adolescents with higher-risk sexual behaviors also demonstrated greater functional connectivity between the precuneus and the temporoparietal junction bilaterally, dorsal medial prefrontal cortex, and left anterior insula/ventrolateral prefrontal cortex. The greater activation and functional connectivity in self-referential, social reward, and affective processing regions among higher sexual risk adolescents underscores the importance of social influence underlying sexual risk behaviors. Furthermore, results suggest an orientation towards and sensitivity to social rewards among youth engaging in higher-risk sexual behavior, perhaps as a consequence of or vulnerability to such behavior.