No abstract

Biological aging is an inevitable and independent risk factor for a wide array of chronic diseases including cardiovascular and metabolic diseases. Ample evidence has established a pivotal role for interrupted mitochondrial homeostasis in the onset and development of aging-related cardiovascular anomalies. A number of culprit factors have been suggested in aging-associated mitochondrial anomalies including oxidative stress, lipid toxicity, telomere shortening, metabolic disturbance, and DNA damage, with recent findings revealing a likely role for compromised mitochondrial dynamics and mitochondrial quality control machinery such as autophagy. Mitochondria undergo consistent fusion and fission, which are crucial for mitochondrial homeostasis and energy adaptation. Autophagy, in particular, mitochondria-selective autophagy, namely, mitophagy, refers to a highly conservative cellular process to degrade and clear long-lived or damaged cellular organelles including mitochondria, the function of which gradually deteriorates with increased age. Mitochondrial homeostasis could be achieved through a cascade of independent but closely related processes including fusion, fission, mitophagy, and mitochondrial biogenesis. With improved health care and increased human longevity, the ever-rising aging society has imposed a high cardiovascular disease prevalence. It is thus imperative to understand the role of mitochondrial homeostasis in the regulation of lifespan and healthspan. Targeting mitochondrial homeostasis should offer promising novel therapeutic strategies against aging-related complications, particularly cardiovascular diseases.

Defective mitophagy is causally linked to obesity complications. Here, we identified an interaction between mitophagy protein FUNDC1 (FUN14 domain containing 1) and receptor subunit of human SCF (SKP1/cullin/F-box protein) ubiquitin ligase complex FBXL2 as a gatekeeper for mitochondrial Ca2+ homeostasis through degradation of IP3R3 (inositol 1,4,5-trisphosphate receptor type 3). Loss of FUNDC1 in FUNDC1−/− mice accentuated high-fat diet–induced cardiac remodeling, functional and mitochondrial anomalies, cell death, rise in IP3R3, and Ca2+ overload. Mass spectrometry and co-immunoprecipitation analyses revealed an interaction between FUNDC1 and FBXL2. Truncated mutants of Fbox (Delta-F-box) disengaged FBXL2 interaction with FUNDC1. Activation or transfection of FBXL2, inhibition of IP3R3 alleviated, whereas disruption of FBXL2 localization sensitized lipotoxicity-induced cardiac damage. FUNDC1 deficiency accelerated and decelerated palmitic acid–induced degradation of FBXL2 and IP3R3, respectively. Our data suggest an essential role for interaction between FUNDC1 and FBXL2 in preserving mitochondrial Ca2+ homeostasis and cardiac function in obese hearts.

Background Coronary diffuse disease associates with poor outcomes, but little is known about its role after percutaneous coronary intervention (PCI). We aimed to investigate the prognostic implication of pre‐PCI focal or diffuse disease patterns combined with post‐PCI quantitative flow ratio (QFR). Methods and Results Pre‐PCI QFR derived pullback pressure gradient (PPG) (QFR‐PPG) was measured to assess physiological disease patterns for 1685 included vessels; the vessels were classified according to dichotomous pre‐PCI QFR‐PPG and post‐PCI QFR. Vessel‐oriented composite outcome, a composite of vessel‐related ischemia‐driven revascularization, vessel‐related myocardial infarction, or cardiac death at 2 years was compared among these groups. Vessels with low pre‐PCI PPG (3.9% versus 2.0%, hazard ratio [HR], 1.93; 95% CI, 1.08–3.44; P =0.02) or low post‐PCI QFR (9.8% versus 2.7%, HR, 3.78; 95% CI, 1.61–8.87; P =0.001) demonstrated higher vessel‐oriented composite outcome risk after stent implantation. Of note, despite high post‐PCI QFR achieved, vessels with low pre‐PCI QFR‐PPG presented higher risk of vessel‐oriented composite outcome than those with high pre‐PCI QFR‐PPG (3.7% versus 1.8%, HR, 2.03; 95% CI, 1.09–3.76; P =0.03) and pre‐PCI QFR‐PPG demonstrated direct prognostic effect not mediated by post‐PCI QFR. Integration of groups classified by pre‐PCI QFR‐PPG and post‐PCI QFR showed significantly higher discriminant and reclassification abilities than clinical factors (C‐index 0.77 versus 0.72, P =0.03; integrated discrimination improvement 0.93%, P =0.04; net reclassification index 0.33, P =0.02). Conclusions Prognostic value of pre‐PCI focal or diffuse disease patterns assessed by QFR‐PPG index was retained even after successful PCI, which is mostly explained by its direct effect that was not mediated by post‐PCI QFR. Integration of both pre‐PCI and post‐PCI physiological information can provide better risk stratification in vessels with stent implantation. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05104580.

Doxorubicin (DOX) is an effective anti-cancer anthracyclines chemotherapy drug with its potentially life-threatening cardiotoxicity severely limiting its clinical application. Mitochondrial damage-induced cardiomyocyte death is considered an essential cue for DOX cardiotoxicity. FUN14 domain containing 1 (FUNDC1) is a mitochondrial membrane protein participating in the regulation of mitochondrial integrity in multiple diseases although its role in DOX cardiomyopathy remains elusive. Here we examined whether PANoptosis, a novel type of programmed cell death closely associated with mitochondrial damage, was involved in DOX-induced heart injury, and whether FUNDC1 regulated cardiomyocyte PANoptosis. FUNDC1 was downregulated in heart tissues in patients with dilated cardiomyopathy (DCM) and DOX-challenged mice. FUNDC1 deficiency aggravated DOX-induced cardiac dysfunction, mitochondrial injury and cardiomyocyte PANoptosis. Further examination revealed that FUNDC1 countered against cytoplasmic release of mitochondrial DNA (mtDNA) and activation of PANoptosome through interaction with mitochondrial Tu translation elongation factor (TUFM), a key factor in the translational expression and repair of mitochondrial DNA, via its 96–133 amino acid domain. TUFM intervention reversed FUNDC1-elicited protection against DOX-induced mtDNA cytosolic release and cardiomyocyte PANoptosis. These findings shed light towards the protective role of FUNDC1 against DOX cardiotoxicity and cardiomyocyte PANoptosis, which provides a potentially therapeutic approach for Dox induced cardiotoxicity.