Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP, but OXPHOS also supports biosynthesis during proliferation. In contrast, the role of OXPHOS during quiescence, beyond ATP production, is not well understood. Using mouse models of inducible OXPHOS deficiency in all cell types or specifically in the vascular endothelium that negligibly relies on OXPHOS-derived ATP, we show that selectively during quiescence OXPHOS provides oxidative stress resistance by supporting macroautophagy/autophagy. Mechanistically, OXPHOS constitutively generates low levels of endogenous ROS that induce autophagy via attenuation of ATG4B activity, which provides protection from ROS insult. Physiologically, the OXPHOS-autophagy system (i) protects healthy tissue from toxicity of ROS-based anticancer therapy, and (ii) provides ROS resistance in the endothelium, ameliorating systemic LPS-induced inflammation as well as inflammatory bowel disease. Hence, cells acquired mitochondria during evolution to profit from oxidative metabolism, but also built in an autophagy-based ROS-induced protective mechanism to guard against oxidative stress associated with OXPHOS function during quiescence.Abbreviations: AMPK: AMP-activated protein kinase; AOX: alternative oxidase; Baf A: bafilomycin A1; CI, respiratory complexes I; DCF-DA: 2',7'-dichlordihydrofluorescein diacetate; DHE: dihydroethidium; DSS: dextran sodium sulfate; ΔΨmi: mitochondrial inner membrane potential; EdU: 5-ethynyl-2'-deoxyuridine; ETC: electron transport chain; FA: formaldehyde; HUVEC; human umbilical cord endothelial cells; IBD: inflammatory bowel disease; LC3B: microtubule associated protein 1 light chain 3 beta; LPS: lipopolysaccharide; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; mtDNA: mitochondrial DNA; NAC: N-acetyl cysteine; OXPHOS: oxidative phosphorylation; PCs: proliferating cells; PE: phosphatidylethanolamine; PEITC: phenethyl isothiocyanate; QCs: quiescent cells; ROS: reactive oxygen species; PLA2: phospholipase A2, WB: western blot.
- MeSH
- adenosintrifosfát metabolismus MeSH
- autofagie * MeSH
- cystein metabolismus MeSH
- dextrany metabolismus MeSH
- dýchání MeSH
- endoteliální buňky metabolismus MeSH
- fibroblasty metabolismus MeSH
- formaldehyd metabolismus MeSH
- fosfatidylethanolaminy metabolismus MeSH
- idiopatické střevní záněty * metabolismus MeSH
- isothiokyanatany MeSH
- lidé MeSH
- lipopolysacharidy metabolismus MeSH
- mitochondriální DNA metabolismus MeSH
- mitochondrie metabolismus MeSH
- mTORC1 metabolismus MeSH
- myši MeSH
- proteinkinasy aktivované AMP metabolismus MeSH
- proteiny asociované s mikrotubuly metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- sirolimus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Context: The influence of co-morbid conditions on the outcome of acute methanol poisoning in mass poisoning outbreaks is not known.Objective: The objective of this is to study the impact of burden of co-morbidities, complications, and methanol-induced brain lesions on hospital, follow-up, and total mortality.Methods: All patients hospitalized with methanol poisoning during a mass poisoning outbreak were followed in a prospective cohort study until death or final follow-up after 6 years. The age-adjusted Charlson co-morbidity index (ACCI) score was calculated for each patient. A multivariate Cox regression model was used to calculate the adjusted hazards ratio (HR) for death. The survival was modeled using the Kaplan-Meier method.Results: Of 108 patients (mean age with SD 50.9 ± 2.6 years), 24 (54.4 ± 5.9 years) died during hospitalization (mean survival with SD 8 ± 4 days) and 84 (49.9 ± 3.0 years; p = .159) were discharged, including 27 with methanol-induced brain lesions. Of the discharged patients, 15 (56.3 ± 6.8 years) died during the follow-up (mean survival 37 ± 11 months) and 69 (48.5 ± 3.3 years; p = .044) survived. The hospital mortality was 22%, the follow-up mortality was 18%; the total mortality was 36%. Cardiac/respiratory arrest, acute respiratory failure, multiorgan failure syndrome, and arterial hypotension increased the HR for hospital and total (but not follow-up) mortality after adjustment for age, sex, and arterial pH (all p < .05). All patients who died in the hospital had at least one complication. A higher ACCI score was associated with greater total mortality (HR 1.22; 1.00-1.48 95% CI; p = .046). Of those who died, 35 (90%) had a moderate-to-high ACCI. The Kaplan-Meier curve demonstrated that patients with a high ACCI had greater follow-up mortality compared to ones with low (p = .027) or moderate (p = .020) scores. For the patients who died during follow-up, cancers of different localizations were responsible for 7/15 (47%) of the deaths.Conclusions: The character and number of complications affected hospital but not follow-up mortality, while the burden of co-morbidities affected follow-up mortality. Methanol-induced brain lesions did not affect follow-up mortality. Relatively high cancer mortality rate may be associated with acute exposure to metabolic formaldehyde produced by methanol oxidation.
- MeSH
- dospělí MeSH
- epidemický výskyt choroby statistika a číselné údaje MeSH
- formaldehyd metabolismus otrava MeSH
- hospitalizace statistika a číselné údaje MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- longitudinální studie MeSH
- methanol farmakokinetika otrava MeSH
- míra přežití MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mortalita v nemocnicích * MeSH
- následné studie MeSH
- otrava epidemiologie mortalita MeSH
- prospektivní studie MeSH
- rizikové faktory MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- acidóza MeSH
- antidota klasifikace terapeutické užití MeSH
- biologické markery MeSH
- estery kyseliny mravenčí metabolismus škodlivé účinky toxicita MeSH
- ethanol aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- formaldehyd metabolismus škodlivé účinky toxicita MeSH
- formiáty metabolismus škodlivé účinky toxicita MeSH
- klinické laboratorní techniky metody využití MeSH
- kyselina listová aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- methanol farmakokinetika škodlivé účinky toxicita MeSH
- otrava diagnóza komplikace terapie MeSH
- příznaky a symptomy MeSH
- pyrazoly aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- urgentní zdravotnické služby metody organizace a řízení MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH
- MeSH
- acetylcholinesterasa metabolismus MeSH
- adrenergní vlákna enzymologie patologie MeSH
- arterie inervace metabolismus MeSH
- formaldehyd metabolismus MeSH
- katecholaminy metabolismus MeSH
- kočky MeSH
- králíci MeSH
- krční mandle inervace krevní zásobení metabolismus MeSH
- serotonin metabolismus MeSH
- zvířata MeSH
- Check Tag
- kočky MeSH
- králíci MeSH
- zvířata MeSH
- MeSH
- formaldehyd metabolismus MeSH
- formiáty analogy a deriváty moč MeSH
- lidé MeSH
- moč analýza MeSH
- nemoci z povolání MeSH
- Check Tag
- lidé MeSH
