bims-lypmec 2025-08-17 papers

Nat Commun. 2025 Aug 09. 16(1): 7367

Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.

Mutations that disrupt the clearance of damaged mitochondria via mitophagy are causative for neurological disorders including Parkinson's. Here, we identify a Mitophagic Stress Response (MitoSR) activated by mitochondrial damage in neurons and operating in parallel to canonical Pink1/Parkin-dependent mitophagy. Increasing levels of mitochondrial stress trigger a graded response that induces the concerted degradation of negative regulators of autophagy including Myotubularin-related phosphatase (MTMR)5, MTMR2 and Rubicon via the ubiquitin-proteasome pathway and selective proteolysis. MTMR5/MTMR2 inhibit autophagosome biogenesis; consistent with this, mitochondrial engulfment by autophagosomes is enhanced upon MTMR2 depletion. Rubicon inhibits lysosomal function, blocking later steps of neuronal autophagy; Rubicon depletion relieves this inhibition. Targeted depletion of both MTMR2 and Rubicon is sufficient to enhance mitophagy, promoting autophagosome biogenesis and facilitating mitophagosome-lysosome fusion. Together, these findings suggest that therapeutic activation of MitoSR to induce the selective degradation of negative regulators of autophagy may enhance mitochondrial quality control in stressed neurons.

DOI: https://doi.org/10.1038/s41467-025-62379-5

Curr Cardiol Rep. 2025 Aug 15. 27(1): 128

Metabolic Regulation of Cardiovascular Aging.

Michael Gao, Toren Finkel.

PURPOSE OF REVIEW: Metabolic changes can play a critical role in the structural and functional decline of the aging cardiovascular system. In this review, we examine how key metabolic pathways and regulatory mechanisms influence cardiovascular aging, highlighting recent studies into metabolic flexibility, mitochondrial function, nutrient sensing, and energy utilization in the aging heart. Potential metabolic-based interventions to mitigate cardiac aging are also discussed.
RECENT FINDINGS: Various metabolic changes have been observed in the aging heart. Impaired metabolic flexibility, as seen by reduced fatty acid oxidation with an increased reliance on glucose, is observed. Mitochondrial dysfunction and increased oxidative stress in aged cardiomyocytes may lead to energy deficits, contributing to myocardial fibrosis and diastolic dysfunction. Accelerated cardiovascular aging is also connected to the dysregulation of nutrient-sensing pathways- such as AMP-activated protein kinase (AMPK), sirtuins, and the mechanistic target of rapamycin (mTOR). Enhancing the age-dependent decline in autophagy and mitophagy, which clears damaged organelles, appears to preserve cardiac function in aging. Recent studies have shown that interventions such as caloric restriction, exercise, and metformin can favorably remodel cardiac metabolism and delay age-related cardiac deterioration. Metabolic changes, including energy substrate shifts, mitochondrial oxidative stress, and impaired nutrient signaling, play a direct role in cardiovascular aging. Targeting these metabolic factors and pathways holds promise for alleviating age-associated cardiac dysfunction. Recent studies focusing on lifestyle or pharmacologic means of metabolic modulation provide and outline for the promotion of healthy cardiovascular aging, thereby reducing the burden of cardiovascular disease in the growing aging population.

Keywords: Autophagy; Cardiovascular aging; Metabolic flexibility; Metabolism; Mitochondrial dysfunction; Nutrient sensing

DOI: https://doi.org/10.1007/s11886-025-02279-8

Diabetol Metab Syndr. 2025 Aug 14. 17(1): 334

Deep phenotyping of a modified diabetic cardiomyopathy mouse model which reflects clinical disease progression.

Narainrit Karuna, Lauren Kerrigan, Kevin Edgar, Oisin Cappa, David Simpson, Claire Tonry, David J Grieve, Chris J Watson.

Diabetic cardiomyopathy (DbCM) is a progressive disease and common complication of metabolic diabetes. It is characterised by onset of cardiac structural and functional impairments and can lead to direct development of clinical heart failure (HF) or predispose to hypertensive/ischaemic stress. DbCM is a complex disease which involves several metabolic and pathogenic factors. We characterised an established high-fat diet/streptozotocin (HFD/STZ)-induced DbCM model incorporating typical features of human disease to determine its suitability for preclinical evaluation of novel therapeutics prior to advancement to human trials. Male C57BL/6J mice were randomised to HFD and single-dose STZ (100 mg/kg) or control diet (CD) and vehicle. HFD/STZ mice developed type 2 diabetes mellitus (T2DM), reflected by high fasting blood glucose and HbA1c levels, reduced β-cell function, and increased insulin resistance without systolic blood pressure alteration. Furthermore, HFD/STZ mice displayed progressive diastolic dysfunction, evidenced by decreased MV E/A ratio, together with elevated chronic left ventricular (LV) filling pressure parameters, measured by left atrial (LA) area and LA volume, compared to controls, in parallel with LV hypertrophy and fibrosis. Monocyte trafficking into diabetic hearts was identified by single-nuclei RNA sequencing analysis, which revealed an interferon-α response in DbCM mice, whilst plasma proteomics confirmed the involvement of inflammatory processes with elevated plasma C-reactive protein in DbCM progression. Taken together, our HFD/STZ-induced DbCM model exhibits a unique DbCM pre-clinical phenotype reflecting a "triple-hit" of human DbCM features comprising (1) T2DM with insulin resistance, (2) progressive diastolic dysfunction and LV remodelling, and (3) metabolic inflammation. This improved HFD/STZ-induced DbCM model supports clinically relevant research on DbCM progression from early stages to cardiac dysfunction and remodelling as the basis for translational investigation.

Keywords: Cardiac fibrosis; Diabetic cardiomyopathy; Diastolic dysfunction; Heart failure; Metabolic syndrome

DOI: https://doi.org/10.1186/s13098-025-01913-3

Nat Commun. 2025 Aug 09. 16(1): 7360

Opposing regulation of the K63-linked polyubiquitination of RIPK3 by SMURF1 and USP5 in necroptosis.

Chi Hyun Hwang, Minhong Lee, Ju Won Kim, Young Woo Nam, Gyuho Hwang, Hyun Sung Ryu, Jinho Seo, Eun-Woo Lee, Hyuk Wan Ko, Jaewhan Song.

Receptor-interacting protein kinase 3 (RIPK3), a key regulator of necroptosis, is modulated by ubiquitination through various E3 ligases and deubiquitinases. However, the effects of different polyubiquitination processes on RIPK3 and necroptosis remain unclear. Using a proteomic approach, we identify SMAD Ubiquitination Regulatory Factor 1 (SMURF1) and Ubiquitin-specific peptidase 5 (USP5) as crucial regulators of RIPK3 within the necrosome during necroptosis. SMURF1 facilitates K63 polyubiquitination of RIPK3 at lysine 55 and 363, inhibiting necrosome formation and necroptosis. SMURF1 depletion accelerates necroptosis, while the reintroduction of functional SMURF1 reverses this. Conversely, USP5 acts as a deubiquitinase, removing K63 ubiquitin chains and promoting necroptosis. Reducing SMURF1, using a RIPK3 mutant defective in SMURF1-mediated ubiquitination, or overexpressing USP5 enhances necroptosis in leukaemia cells, leading to reduced tumour growth in xenograft models treated with birinapant and emricasan. These findings highlight the opposing regulation of K63-linked polyubiquitination of RIPK3 by SMURF1 and USP5 in necroptosis.

DOI: https://doi.org/10.1038/s41467-025-62723-9