bims-tofagi 2025-07-06 papers

Issue of 2025–07–06
five papers selected by
Michele Frison, University of Cambridge

Trends Endocrinol Metab. 2025 Jul 02. pii: S1043-2760(25)00120-1. [Epub ahead of print]

Neuronal glycolysis meets mitophagy to govern organismal wellbeing.

Daniel Jimenez-Blasco, Rebeca Lapresa, Jesus Agulla, Angeles Almeida, Juan P Bolaños.

Neurons are exceptionally energy-demanding cells but have limited energy storage, relying on a constant supply of fuel and oxygen. Although glucose is the brain's main energy source, neurons reduce glycolysis under normal conditions. This surprising strategy helps to protect mitochondria by preserving nicotinamide-adenine dinucleotide (NAD+), a vital cofactor consumed by glycolysis. NAD+ is needed for sirtuin-driven mitophagy, a process that removes damaged mitochondria. By saving NAD+, neurons can maintain healthy, energy-efficient mitochondria. These mitochondria then use alternative fuels such as lactate and ketone bodies from astrocytes. Here, we discuss the way in which this balance between reduced glycolysis and active mitophagy supports brain function and overall metabolic health, highlighting a sophisticated system that prioritizes mitochondrial quality for long-term cognitive performance and systemic homeostasis.

Keywords: NAD; glycolysis; mitophay; neuron; organismal wellbeing

DOI: https://doi.org/10.1016/j.tem.2025.05.005

Nat Commun. 2025 Jul 01. 16(1): 5465

Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.

Nuo Sun, Hayley Barta, Samhita Chaudhuri, Kangxuan Chen, Jiacheng Jin, Hongke Luo, Mingchong Yang, Judith Krigman, Ruohan Zhang, Shridhar Sanghvi, Shiori Sekine, Hannah Sanders, Dominic Kolonay, Mudra Patel, Kedryn Baskin, Harpreet Singh, Pengyi Zhang, Gang Xin, Toren Finkel.

The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) to sustain its high energy demands. FAO deficiencies can cause muscle weakness, cardiomyopathy, and, in severe cases, neonatal/infantile mortality. Although FAO deficits are thought to induce mitochondrial stress and activate mitophagy, a quality control mechanism that eliminates damaged mitochondria, the mechanistic link in the heart remains unclear. Here we show that mitophagy is unexpectedly suppressed in FAO-deficient hearts despite pronounced mitochondrial stress, using a cardiomyocyte-specific carnitine palmitoyltransferase 2 (CPT2) knockout model. Multi-omics profiling reveals impaired PINK1/Parkin signaling and dysregulation of PARL, a mitochondrial protease essential for PINK1 processing. Strikingly, deletion of USP30, a mitochondrial deubiquitinase that antagonizes PINK1/Parkin function, restores mitophagy, improves cardiac function, and significantly extends survival in FAO-deficient animals. These findings redefine the mitophagy response in FAO-deficient hearts and establish USP30 as a promising therapeutic target for metabolic cardiomyopathies and broader heart failure characterized by impaired FAO.

DOI: https://doi.org/10.1038/s41467-025-60670-z

FASEB J. 2025 Jul 15. 39(13): e70792

ATF7-PINK1 Axis Governs Mitophagy and Intestinal Inflammation in Ulcerative Colitis.

Yidong Chen, Xiaopeng Zhang, Junrong Li, Fang Liu, Qi Yu, Jiamin Li, Liangru Zhu.

Ulcerative colitis (UC), a chronic inflammatory bowel disease, is marked by sustained inflammation and excessive apoptosis of intestinal epithelial cells (IECs). Despite progress in understanding UC pathogenesis, the role of activating transcription factors (ATFs) in disease progression remains elusive. Here, we profile the expression of ATF family members (ATF1-ATF7) in the colonic mucosa of UC patients and identify ATF7 as a critical regulator of mitophagy through its control of PTEN-induced kinase 1 (PINK1). Expression levels of ATF1-ATF7 were quantified in colonic mucosal samples from UC patients (n = 219) and healthy controls (n = 105) via quantitative PCR. Using IEC-specific ATF7 knockout mouse models and human CCD 841 CoN colonic epithelial cells, we employed ChIP-seq, dual-luciferase assays, transmission electron microscopy, and immunofluorescence to elucidate their roles in mitophagy and disease progression. Clinical correlation between ATF7 expression and disease severity was assessed using the Mayo score. ATF7 expression was significantly reduced in UC patients and inversely correlated with disease severity. Mechanistically, ATF7 was identified as a direct transcriptional activator of PINK1, a key mitophagy regulator. Loss of ATF7 or PINK1 disrupted mitophagy, exacerbating mitochondrial dysfunction, IEC apoptosis, and colonic inflammation in vivo and in vitro. Our findings uncover a pivotal ATF7-PINK1 axis that governs mitophagy and limits UC progression. The inverse correlation between ATF7 expression and UC severity highlights its potential as a therapeutic target, offering new avenues for intervention in this debilitating disease.

Keywords: ATF7; PINK1; mitophagy; ulcerative colitis

DOI: https://doi.org/10.1096/fj.202500813R

Cell Death Dis. 2025 Jul 05. 16(1): 494

The role of cardiolipin in mitochondrial dynamics and quality control in neuronal ischemia/reperfusion injury.

Katlynn J Emaus, Garrett M Fogo, Joseph M Wider, Thomas H Sanderson.

Stroke and cardiac arrest claim the lives of millions worldwide each year emphasizing the importance of understanding this injury cascade. These pathologies present as a 'two hit' injury termed ischemia/reperfusion (I/R) injury. The primary injury is the initial disruption of blood flow and ischemic state while the secondary injury, paradoxically, being the return of blood flow and oxygen availability. The injury caused by reperfusion presents a viable window for therapeutic intervention, stressing the importance of understanding this injury pathology. Constantly undergoing fission and fusion, mitochondria are dynamic organelles that play a vital role in maintaining cell health and are highly susceptible to I/R injury. Following I/R injury, disrupted mitochondrial dynamics and quality control ultimately lead to a dysfunctional mitochondrial network, energy depletion and eventually cell death. While mitochondrial dynamics and quality control have been studied extensively in the realm of I/R injuries, the role of mitochondrial lipids is emerging as an important component of injury progression. The inner mitochondrial membrane lipid, cardiolipin has been demonstrated to play an integral role in maintaining mitochondrial quality control, dynamics and energy production. In response to oxidative stress, cardiolipin has been shown to interact with several important proteins involved in mitochondrial dynamics while also contributing to integral signaling cascades. This review will highlight the role of cardiolipin in mitochondrial dynamics and quality control in response to neuronal I/R injury.

DOI: https://doi.org/10.1038/s41419-025-07786-8

Theranostics. 2025 ;15(14): 6753-6767

RAB7 protects against ischemic heart failure via promoting non-canonical TUFM mitophagy pathway.

Yuling Sun, Wei Wang, Mingyan Li, Wen Guan, Zhimin Gao, Luping Wang, Guanlan Lou, Ao Shen, Jiangbin Wu, Xiyong Yu, Panxia Wang, Xiaoqian Wu.

Rationale: Cardiomyocyte apoptosis critically contributes to ischemic heart failure (IHF) progression. While the endosome-lysosome system governs cellular homeostasis, the functional significance of its master regulator RAB7 in cardiac pathophysiology remains unexplored. Methods: Using myocardial infarction (MI) models via left anterior descending coronary artery ligation in cardiomyocyte-specific RAB7 knockout mice and adeno-associated virus-mediated RAB7 overexpression models, we assessed cardiac function and adverse remodeling through echocardiography and pathophysiological assessment. Mitophagy flux was quantified using mt-Keima mice and confocal imaging. Molecular mechanisms were dissected through immunoprecipitation coupled with mass spectrometry (IP-MS) analysis and molecular experiment validation. Results: RAB7 expression decreased in ischemic myocardium. Cardiomyocyte-specific RAB7 ablation exacerbated while RAB7 overexpression attenuated post-MI cardiac dysfunction and maladaptive remodeling. RAB7 enhanced mitophagic clearance of damaged mitochondria, reducing cardiomyocyte apoptosis under ischemic stress both in vitro and in vivo. Mechanistically, TUFM, a mitochondrial translation elongation factor, was identified as a novel effector of RAB7. RAB7 facilitated the recruitment of TUFM and LC3 to damaged mitochondria, thereby enhancing mitophagy. TUFM knockdown significantly diminished the protective effects of RAB7 on mitophagy and cardiomyocyte survival. Finally, administration of ML-098, a chemical RAB7 activator, promoted mitophagy and mitigated IHF progression in mice. Conclusion: We identify RAB7 as a novel coordinator of cardioprotective mitophagy through TUFM-mediated machinery assembly. The RAB7-TUFM axis represents a therapeutic target for IHF that warrants further clinical evaluation.

Keywords: RAB7; TUFM; mitophagy; myocardial infarction

DOI: https://doi.org/10.7150/thno.104124