Background:The mechanisms initiating protein acylation in mitochondria are unknown. Results: The pH and acyl-CoA concentrations of the mitochondrial matrix are sufficient to cause protein lysine acetylation and succinylation. Conclusion: Protein acylation in mitochondria may be a nonenzymatic event facilitated by the alkaline pH and high acyl-CoA concentrations. Significance: The mitochondrial deacylases SIRT3 and SIRT5 may have evolved to regulate nonenzymatic protein acylation.

ImportanceSARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.ObjectiveTo develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.Design, Setting, and ParticipantsProspective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.ExposureSARS-CoV-2 infection.Main Outcomes and MeasuresPASC and 44 participant-reported symptoms (with severity thresholds).ResultsA total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.Conclusions and RelevanceA definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Background-Doxorubicin is used to treat childhood and adult cancer. Doxorubicin treatment is associated with both acute and chronic cardiotoxicity. The cardiotoxic effects of doxorubicin are cumulative, which limits its chemotherapeutic dose. Free radical generation and p53-dependent apoptosis are thought to contribute to doxorubicin-induced cardiotoxicity. Methods and Results-Adult transgenic (MHC-CB7) mice expressing cardiomyocyte-restricted dominant-interfering p53and their nontransgenic littermates were treated with doxorubicin (20 mg/kg cumulative dose Key Words: heart failure Ⅲ apoptosis Ⅲ myocytes A nthracyclines such as doxorubicin, daunomycin, epirubicin, and idarubicin are widely used and highly successful anticancer chemotherapeutic drugs. Unfortunately, these drugs also induce acute cardiotoxicity, which is characterized by hypotension, tachycardia, arrhythmia, and transient depression of left ventricular function. [1][2][3][4] In addition, high cumulative doses are associated with late-onset cardiomyopathy that is refractory to standard treatment. It is widely thought that free radical-induced mitochondrial damage contributes to doxorubicin-induced cardiotoxicity. 5 In addition, doxorubicin can induce DNA damage, inhibit DNA and protein synthesis, promote myofiber degeneration, inhibit transcription of specific gene programs, and induce cardiomyocyte apoptosis via a caspase-3-dependent mechanism. Because doxorubicin can interfere with many different intracellular processes, it has proven difficult to determine the molecular mechanism of its acute and chronic cardiotoxicity. Clinical Perspective p 106Numerous studies have shown that doxorubicin-induced cardiomyocyte apoptosis is associated with increased expression of the p53 tumor suppressor protein. Moreover, reduction of p53 activity via genetic deletion 6 or chemical inhibition 7 is cardioprotective during short-term doxorubicin treatment. To further characterize the role of p53 in acute doxorubicin-induced cardiotoxicity, MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes) 8 were studied 7 days after the initiation of treatment. Cardiac function was improved, with a concomitant reduction in cardiomyocyte apoptosis, in the MHC-CB7 mice compared with their doxorubicin-treated nontransgenic siblings. Surprisingly, expression of the MHC-CB7 transgene also markedly blunted the doxorubicin-induced reduction of cardiac mass observed in nontransgenic mice. Western blot analyses indicated that doxorubicin treatment reduced the level of activated mammalian target of rapamycin (mTOR) in nontransgenic mice. mTOR is a serine/threonine protein kinase that regulates protein translation and cell growth. 9 Expression of the MHC-CB7 transgene blocked doxorubicin-induced reduction of mTOR activity. To establish the role of mTOR signaling in doxorubicin-induced cardiotoxicity, mice expressing constitutively active mTOR in the myocardium (MHC-mTORca mice) 10 were subjected to doxorubicin treatment. Expression of the MHC-mTORca transgene was suffi...

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There is an intimate interplay between cellular metabolism and the pathophysiology of disease. Mitochondria are essential to maintaining and regulating metabolic function of cells and organs. Mitochondrial dysfunction is implicated in diverse diseases, such as cardiovascular disease, diabetes and metabolic syndrome, neurodegeneration, cancer and aging. Multiple reversible post-translational protein modifications are located in the mitochondria that are responsive to nutrient availability and redox conditions, and which can act in protein-protein interactions to modify diverse mitochondrial functions. Included in this are physiologic redox signaling via reactive oxygen and nitrogen species, phosphorylation, O-GlcNAcylation, acetylation, and succinylation, among others. With the advent of mass proteomic screening techniques, there has been a vast increase in the array of known mitochondrial post-translational modifications and their protein targets. The functional significance of these processes in disease etiology, and the pathologic response to their disruption, are still under investigation. However, many of these reversible modifications act as regulatory mechanisms in mitochondria and show promise for mitochondrial-targeted therapeutic strategies. This review addresses the current knowledge of post-translational processing and signaling mechanisms in mitochondria, and their implications in health and disease.