Peroxisomal support of mitochondrial respiratory efficiency promotes ER stress survival.

Endoplasmic reticulum stress (ERS) occurs when cellular demand for protein folding exceeds the capacity of the organelle. Adaptation and cell survival in response to ERS requires a critical contribution by mitochondria and peroxisomes. During ERS responses, mitochondrial respiration increases to ameliorate reactive oxygen species (ROS) accumulation. We now show in yeast that peroxisome abundance also increases to promote an adaptive response. In pox1Δ cells, which are defective in peroxisomal ß-oxidation of fatty acids, the respiratory response to ERS is impaired and ROS accrues. However, the respiratory response to ERS is rescued and ROS production is mitigated in pox1Δ cells overexpressing Mpc1, the mitochondrial pyruvate carrier that provides another source of acetyl CoA to fuel the tricarboxylic acid cycle and oxidative phosphorylation. Using proteomics, select mitochondrial proteins were identified that undergo upregulation upon ERS to remodel the respiratory machinery. The abundance of several peroxisome-based proteins was also increased, corroborating the role of peroxisomes in ERS adaptation. Finally, ERS stimulates assembly of respiratory complexes into higher-order supercomplexes, underlying increased electron transfer efficiency. Our results highlight peroxisomal and mitochondrial support for ERS adaptation to favor cell survival.

Retrograde signaling mediates an adaptive survival response to endoplasmic reticulum stress in Saccharomyces cerevisiae.

One major cause of endoplasmic reticulum (ER) stress is homeostatic imbalance between biosynthetic protein folding and protein folding capacity. Cells utilize mechanisms such as the unfolded protein response (UPR) to cope with ER stress. Nevertheless, when ER stress is prolonged or severe, cell death may occur, accompanied by production of mitochondrial reactive oxygen species (ROS). Using a yeast model (Saccharomyces cerevisiae), we describe an innate, adaptive response to ER stress to increase select mitochondrial proteins, O2 consumption and cell survival. The mitochondrial response allows cells to resist additional ER stress. The ER stress-induced mitochondrial response is mediated by activation of retrograde (RTG) signaling to enhance anapleurotic reactions of the tricarboxylic acid cycle. Mitochondrial response to ER stress is accompanied by inactivation of the conserved TORC1 pathway, and activation of Snf1/AMPK, the conserved energy sensor and regulator of metabolism. Our results provide new insight into the role of respiration in cell survival in the face of ER stress, and should help in developing therapeutic strategies to limit cell death in disorders linked to ER stress.This article has an associated First Person interview with the first author of the paper.

Black Americans have worse stroke outcome compared with non-Hispanic whites.

INTRODUCTION: We studied racial differences in post-stroke outcomes using a prospective, population-based cohort of stroke survivors as part of the Brain Attack Surveillance in Corpus Christi (BASIC) project. METHODS: Neurologic (NIHSS, range of 0-42, higher scores are worse), functional (ADLs/IADLs, range 1-4, higher scores are worse), and cognitive (3MSE, range 0-100, higher scores are better) outcomes were measured 90 days after stroke. Cox proportional hazards and negative binomial linear regression models were used to examine the associations between race and 90-day all-cause mortality and NIHSS, respectively, whereas linear regression was used for ADLs/IADLs and 3MSE scores. Covariates included demographics, initial NIHSS, comorbidities, prior stroke history, tPA treatment status, pre-stroke disability, and pre-stroke cognition. The mortality model was also adjusted for DNR status. RESULTS: At 90 days post-stroke, Black American individuals (BAs) (n = 122) had a median (IQR) NIHSS of 2 (1,6) compared to NIHSS of 1 (0,3) in non-Hispanic White American individuals (NHWs) (n = 795). BAs had a median (IQR) ADL/IADL score of 2.41 (1.50, 3.39) compared to 2.00 (1.27, 2.95) in NHWs. BAs scored a median of 84 (75, 92) on the 3MSE compared to NHWs' score of 91.5 (83, 96). Death occurred in 23 (8%) of BAs and 268 (15%) of NHWs within 90 days among those who participated in baseline. After adjustment for covariates, functional outcomes at 90 days were worse in BAs compared to NHWs, with 15.8% (95% CI=5.2, 26.4) greater limitations in ADLs/IADLs and 43.9% (95% CI=12.0, 84.9) greater severity of stroke symptoms. Cognition at 90 days was 6.5% (95% CI=2.4, 10.6) lower in BAs compared to NHWs. BAs had a 35.4% lower (95% CI=-9.8, 61.9) hazard rate of mortality than NHWs. CONCLUSIONS: In this prospective, population-based community sample, BAs had worse neurologic, functional and cognitive outcomes at 90 days compared to NHWs. Future research should investigate how social determinants of health including structural racism, neighborhood factors and access to preventive and recovery services influences these racial disparities.