bims-miptne 2025-05-11 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–05–11
six papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis.
Small-scale protocols to characterize mitochondrial Complex V activity and assembly in peripheral blood mononuclear cells.
Targeting enhanced mitochondrial respiration chain activity as a potential therapeutic approach for endometriosis.
Mitochondrial targets in ischaemic heart disease and heart failure, and their potential for a more efficient clinical translation. A scientific statement of the ESC Working Group on Cellular Biology of the Heart and the ESC Working Group on Myocardial Function.
Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise.
Mitochondrial fatty acid oxidation dysfunction impairs autophagic flux through ATP deficiency-caused lysosomal pH abnormity.

EMBO J. 2025 May 09.

Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis.

Furkan E Oflaz, Alexander I Bondarenko, Michael Trenker, Markus Waldeck-Weiermair, Benjamin Gottschalk, Eva Bernhart, Zhanat Koshenov, Snježana Radulović, Rene Rost, Martin Hirtl, Johannes Pilic, Aditya Karunanithi Nivedita, Adlet Sagintayev, Gerd Leitinger, Bent Brachvogel, Susanne Summerauer, Varda Shoshan-Barmatz, Roland Malli, Wolfgang F Graier.

  Annexin A5 (AnxA5) is a Ca2+-dependent phospholipid-binding protein associated with the regulation of intracellular Ca2+ homeostasis. However, the precise role of AnxA5 in controlling mitochondrial Ca2+ signaling remains elusive. Here, we introduce a novel function of AnxA5 in regulating mitochondrial Ca2+ signaling. Our investigation revealed that AnxA5 localizes at and in the mitochondria and orchestrates intermembrane space Ca2+ signaling upon high Ca2+ elevations induced by ER Ca2+ release. Proximity ligation assays and co-immunoprecipitation revealed a close association but no direct contact of AnxA5 with the voltage-dependent anion channel (VDAC1) in the outer mitochondrial membrane (OMM). In single-cell mitochondrial Ca2+ measurements and electrophysiological recordings, AnxA5 was found to enhance Ca2+ flux through the OMM by promoting the Ca2+-permeable state of VDAC1. By modulating intermembrane space Ca2+ signaling, AnxA5 shapes mitochondrial ultrastructure and influences the dynamicity of the mitochondrial Ca2+ uniporter. Furthermore, by controlling VDAC1's oligomeric state, AnxA5 is protective against cisplatin and selenite-induced apoptotic cell death. Our study uncovers AnxA5 as an integral regulator of VDAC1 in physiological and pathological conditions.

Keywords:  Annexin-A5; Apoptotic Cell Death; Intermembrane Space Ca2⁺ Signaling; VDAC1 Ca2+ Permeability

DOI:  https://doi.org/10.1038/s44318-025-00454-9
PLoS One. 2025 ;20(5): e0323136

Small-scale protocols to characterize mitochondrial Complex V activity and assembly in peripheral blood mononuclear cells.

Kai-Yin Chau, Jan-Willem Taanman, Anthony H V Schapira.

Complex V of the mitochondrial oxidative phosphorylation system is an ATP synthase that plays a pivotal role in the cell's energy transduction. Mutations in genes encoding the multiple protein subunits that constitute complex V cause severe metabolic and neurodegenerative diseases. We present here three complementary assays to assess Complex V activity and assembly in peripheral blood mononuclear cells (PBMCs). The assays involve spectrophotometric and in-gel activity measurements, cytochemical assessment of the mitochondrial transmembrane electrochemical gradient (∆Ѱm) to determine if the enzyme acts forward as an ATP synthase or in reverse as an ATPase, and western blot analysis of clear native gels to evaluate Complex V assembly. The whole process can be performed with 2 × 106 PBMCs isolated from ~2 ml of blood. Our study suggests that PBMCs can serve as a platform for small-scale, minimally invasive investigations of patients suspected of Complex V deficiency or in biomarker research of mitochondrial function.

DOI: https://doi.org/10.1371/journal.pone.0323136
Biochim Biophys Acta Mol Basis Dis. 2025 May 02. pii: S0925-4439(25)00233-9. [Epub ahead of print]1871(6): 167885

Targeting enhanced mitochondrial respiration chain activity as a potential therapeutic approach for endometriosis.

Katarína Kalinová, Benjamin Gottschalk, Martin Hirtl, Julian Ostaku, Sonja Gabrijelčič, Alwin Sokolowski, Ernst Malle, Wolfgang F Graier, Corina T Madreiter-Sokolowski.

  Endometriosis is a chronic condition defined by the presence of endometrial-like tissue outside the uterus. Since endometriotic cells share similarities with cancer cells, including uncontrolled cell growth and invasion, we investigated whether cancer cell-specific rewiring of mitochondrial signaling is also present in endometriotic cells. We utilized the endometriotic cell line 12Z and investigated its mitochondrial function in comparison with the uterine cancer cell line SK-UT-1 and the mammary epithelial cell line hTERT-HME1. We could show that the endometriotic 12Z cells share structural similarities with cancerous SK-UT-1 cells with enhanced colocalization between the endoplasmic reticulum and mitochondria and increased cristae width and density associated with facilitated mitochondrial Ca2+ uptake. However, an increase in the reduction equivalent yield and oxygen consumption rate was exclusively found in 12Z cells, whereas the reduced ΔΨm and the reverse mode of FOF1-ATP synthase were also detected in SK-UT-1 cells. These features rendered both cell types susceptible to quercetin and oligomycin A treatment. We assume that the complexes of the electron transport chain and the FOF1-ATP synthase in reverse mode have a crucial role in maintaining mitochondrial membrane potential and, thereby, mitochondrial integrity of endometriotic 12Z cells. Therefore, targeting the electron transport chain or the reverse mode of FOF1-ATP synthase may represent a promising new treatment strategy for endometriosis.

Keywords:  Endometriosis; F(O)F(1)-ATP synthase; Mitochondrial membrane potential; Organellar interaction; cancer

DOI:  https://doi.org/10.1016/j.bbadis.2025.167885
Eur J Heart Fail. 2025 May 04.

Mitochondrial targets in ischaemic heart disease and heart failure, and their potential for a more efficient clinical translation. A scientific statement of the ESC Working Group on Cellular Biology of the Heart and the ESC Working Group on Myocardial Function.

Melanie Paillard, Mahmoud Abdellatif, Ioanna Andreadou, Christian Bär, Luc Bertrand, Bianca J J M Brundel, Gemma Chiva-Blanch, Sean M Davidson, Dana Dawson, Fabio Di Lisa, Paul Evans, Zoltan Giricz, Derek J Hausenloy, Petra Kleinbongard, Frank Lezoualc'h, Elisa Liehn, Christoph Maack, Ange Maguy, Elizabeth Murphy, Cinzia Perrino, Maurizio Pesce, Peter P Rainer, Katrin Streckfuss-Bömeke, Matthias Thielmann, Rong Tian, Carlo G Tocchetti, Jolanda Van Der Velden, Sophie Van Linthout, Serena Zacchigna, Thomas Krieg.

  Acute myocardial infarction (MI) remains a major cause of death and disability worldwide. No adjuvant treatment has yet been fully validated in patients to limit the progression from the initial tissue damage due to acute MI, to the development of heart failure. However, mitochondria have long been demonstrated to be a key target for cardioprotective strategies to reduce cell death that leads to left ventricular dysfunction and ultimately heart failure. While pre-clinical studies have investigated several mitoprotective strategies targeting different mitochondrial functions, such as oxidative stress or permeability transition pore opening, none have shown successful clinical translation so far. In this European Society of Cardiology scientific statement, we present recent research advances in the understanding of the mitochondrial alterations occurring in MI and in the discovery of key components of mitochondrial structure and function in order to improve drug development. We discuss the reasons for the failure of clinical translation and the remaining obstacles that need to be addressed, including timing of drug administration, tissue bioavailability and efficient mitochondrial targeting, together with the mitochondrial impact derived from risk factors, comorbidities and comedications. Taken together, this scientific statement aims to provides a consensus opinion from clinicians and basic scientists to translate some of the most promising mitoprotective targets into the clinical setting to protect against MI and heart failure.

Keywords:  Cardioprotection; Heart failure; Ischaemia–reperfusion injury; Mitochondria‐targeted drug therapy

DOI:  https://doi.org/10.1002/ejhf.3674
Am J Physiol Heart Circ Physiol. 2025 May 06.

Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise.

Ana Vujic, Amy Koo, Guillaume Bidault, Jan Lj Miljkovic, Andrew M James, Andreas Dannhorn, Xiaowen Duan, Lucy M Davis, Jiro Abe, Joyce Valadares, Jordan J Lee, Alexis Diaz-Vegas, Keira Turner, Richard Goodwin, Daniel J Fazakerley, Antonio Vidal Puig, Michael P Murphy, Thomas Krieg.

  Central to the development of heart failure with preserved ejection fraction (HFpEF) is the redox disruption of metabolic processes, however, the underlying mechanisms are not fully understood. This study utilized a murine model (ND6) carrying a homoplasmic mitochondrial DNA point mutation (ND6 G13997A), which maintains functional NADH oxidation but lacks the site-specific reactive oxygen species (ROS) generation via reverse electron transport (RET). We demonstrate that mice with RET-ROS deficiency have reduced exercise capacity despite higher lean body mass, impaired resilience to high-fat/high-sucrose dietary stress, and cardiac hypertrophy with diastolic dysfunction. Importantly, dobutamine-induced stress elevated succinate levels in the heart, accompanied by RET-ROS production in WT but not in ND6 mice. Furthermore, ND6 mice showed perturbation in metabolite profiles following dobutamine stress. Mechanistically, the ND6 heart had an upregulated expression of fatty acid transport, oxidation, and synthesis genes (CD36, Cpt1b, Acly, Fas, Elovl6 and Scd1) and increased protein levels of lipid metabolism regulators (acetyl-CoA carboxylase and perilipin 2). Interestingly, 8 weeks of forced treadmill running increased acetyl-CoA abundance, alleviated metabolic stress, and improved diastolic function in RET-ROS mutant hearts. In summary, these findings reveal a critical role for RET-ROS in regulating exercise capacity and cardiometabolic health, identifying it as a potentially selective target for modulating cardiac metabolism.

Keywords:  HFpEF; RET-ROS; exercise; lipid metabolism; mitochondria

DOI:  https://doi.org/10.1152/ajpheart.00482.2024
J Nutr Biochem. 2025 May 02. pii: S0955-2863(25)00106-8. [Epub ahead of print] 109943

Mitochondrial fatty acid oxidation dysfunction impairs autophagic flux through ATP deficiency-caused lysosomal pH abnormity.

Yan-Yu Zhang, Ze-Dong Lv, Mai Wang, Jun-Xian Wang, Samwel Mchele Limbu, Fang Qiao, Li-Qiao Chen, Mei-Ling Zhang, Yuan Luo, Zhen-Yu Du.

  Autophagy, a pivotal lysosomal degradation process, plays crucial roles in cellular homeostasis and energy metabolism. Mitochondrial fatty acid oxidation (FAO), a key mitochondrial function, is crucial for energy production. Generally, mitochondrial dysfunction exerts negative effects on autophagy, but the regulatory role of mitochondrial FAO dysfunction on the autophagic process remains unclear. The present study aimed to elucidate the role and mechanism of mitochondrial FAO in regulating autophagy process. We used Nile tilapia (Oreochromis niloticus) as a model and inhibited mitochondrial FAO by dietary mildronate feeding or knocking down carnitine palmitoyltransferase 1a. We found that mitochondrial FAO inhibition enhanced autophagy initiation and lysosomal proliferation accompanied by decreased autophagy degradation activity due to lysosomal acidification abnormity. Moreover, mitochondrial FAO inhibition decreased adenosine triphosphate (ATP) production and elevated adenosine monophosphate (AMP)/ATP promoted autophagy initiation via the AMP-activated protein kinase-serine/threonine kinase 1 pathway. Furthermore, mitochondrial FAO inhibition upregulated peroxisome proliferator-activated receptor alpha and retinoid X receptor alpha protein expression, which promoted transcription factor EB mRNA and its protein expression. Meanwhile, mitochondrial FAO inhibition led to lysosomal alkalinization, which is due to a pH increase caused by v-ATPase V1/V0 imbalance and ATP deficiency from mitochondrial dysfunction. Collectively, our results highlight the role of mitochondrial FAO in maintaining lysosomal homeostasis and autophagic flux through stabilizing lysosomal acidification.

Keywords:  autophagy; fatty acid oxidation inhibition; lysosome; mitochondrial dysfunction; vacuolar ATPase

DOI:  https://doi.org/10.1016/j.jnutbio.2025.109943