bims-miptne 2024-09-08 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2024–09–08
six papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.
Endogenous complement 1q binding protein (C1qbp) regulates mitochondrial permeability transition and post-myocardial infarction remodeling and dysfunction.
Poration of mitochondrial membranes by amyloidogenic peptides and other biological toxins.
Mitochondrial bioenergetics of breast cancer.
Dopaminergic neurons lacking Caspase-3 avoid apoptosis but undergo necrosis after MPTP treatment inducing a Galectin-3-dependent selective microglial phagocytic response.
How mitochondrial dynamics imbalance affects the progression of breast cancer:a mini review.

FEBS Lett. 2024 Sep 03.

Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.

Lishu Guo.

  The opening of the mitochondrial permeability transition pore (PTP), a Ca2+-dependent pore located in the inner mitochondrial membrane, triggers mitochondrial outer membrane permeabilization (MOMP) and induces organelle rupture. However, the underlying mechanism of PTP-induced MOMP remains unclear. Mitochondrial carrier homolog 2 (MTCH2) mediates MOMP process by facilitating the recruitment of tBID to mitochondria. Here, we show that MTCH2 binds to cyclophilin D (CyPD) and promotes the dimerization of F-ATP synthase via interaction with subunit j. The interplay between MTCH2 and subunit j coordinates MOMP and PTP to mediate the occurrence of mitochondrial permeability transition. Knockdown of CyPD, MTCH2 and subunit j markedly sensitizes cells to RSL3-induced ferroptosis, which is prevented by MitoTEMPO, suggesting that mitochondrial permeability transition mediates ferroptosis defense.

Keywords:  F‐ATP synthase; cyclophilin D; ferroptosis; mitochondrial carrier homolog 2; mitochondrial permeability transition

DOI:  https://doi.org/10.1002/1873-3468.15008
J Mol Cell Cardiol. 2024 Aug 30. pii: S0022-2828(24)00140-8. [Epub ahead of print]196 1-11

Endogenous complement 1q binding protein (C1qbp) regulates mitochondrial permeability transition and post-myocardial infarction remodeling and dysfunction.

Manuel Gutiérrez-Aguilar, Paula J Klutho, Rodrigo Aguayo-Ortiz, Lihui Song, Christopher P Baines.

  The mitochondrial permeability transition (MPT) pore regulates necrotic cell death following diverse cardiac insults. While the componentry of the pore itself remains controversial, Cyclophilin D (CypD) has been well-established as a positive regulator of pore opening. We have previously identified Complement 1q-binding protein (C1qbp) as a novel CypD-interacting molecule and a negative regulator of MPT-dependent cell death in vitro. However, its effects on the MPT pore and sensitivity to cell death in the heart remain untested. We therefore hypothesized that C1qbp would inhibit MPT in cardiac mitochondria and protect cardiac myocytes against cell death in vivo. To investigate the effects of C1qbp in the myocardium we generated gain- and loss-of-function mice. Transgenic C1qbp overexpression resulted in decreased complex protein expression and reduced mitochondrial respiration and ATP production but MPT was unaffected. In contrast, while C1qbp+/- mice did not exhibit any changes in mitochondrial protein expression, respiration, or ATP, the MPT pore was markedly sensitized to Ca2+ in these animals. Neither overexpression nor depletion of C1qbp significantly affected baseline heart morphology or function at 3 months of age. When subjected to myocardial infarction, C1qbp transgenic mice exhibited similar infarct sizes and cardiac remodeling to non-transgenic mice, consistent with the lack of an effect on MPT. In contrast, cardiac scar formation and dysfunction were significantly increased in the C1qbp+/- mice compared to C1qbp+/+ controls. Our results suggest that C1qbp is required for normal regulation of the MPT pore and mitochondrial function, and influences cardiac remodeling following MI, the latter more likely being independent of C1qbp effects on the MPT pore.

Keywords:  Mitochondria; Myocardial infarction; Oxidative phosphorylation; Permeability transition

DOI:  https://doi.org/10.1016/j.yjmcc.2024.08.005
J Neurochem. 2024 Aug 30.

Poration of mitochondrial membranes by amyloidogenic peptides and other biological toxins.

Neville Vassallo.

  Mitochondria are essential organelles known to serve broad functions, including in cellular metabolism, calcium buffering, signaling pathways and the regulation of apoptotic cell death. Maintaining the integrity of the outer (OMM) and inner mitochondrial membranes (IMM) is vital for mitochondrial health. Cardiolipin (CL), a unique dimeric glycerophospholipid, is the signature lipid of energy-converting membranes. It plays a significant role in maintaining mitochondrial architecture and function, stabilizing protein complexes and facilitating efficient oxidative phosphorylation (OXPHOS) whilst regulating cytochrome c release from mitochondria. CL is especially enriched in the IMM and at sites of contact between the OMM and IMM. Disorders of protein misfolding, such as Alzheimer's and Parkinson's diseases, involve amyloidogenic peptides like amyloid-β, tau and α-synuclein, which form metastable toxic oligomeric species that interact with biological membranes. Electrophysiological studies have shown that these oligomers form ion-conducting nanopores in membranes mimicking the IMM's phospholipid composition. Poration of mitochondrial membranes disrupts the ionic balance, causing osmotic swelling, loss of the voltage potential across the IMM, release of pro-apoptogenic factors, and leads to cell death. The interaction between CL and amyloid oligomers appears to favour their membrane insertion and pore formation, directly implicating CL in amyloid toxicity. Additionally, pore formation in mitochondrial membranes is not limited to amyloid proteins and peptides; other biological peptides, as diverse as the pro-apoptotic Bcl-2 family members, gasdermin proteins, cobra venom cardiotoxins and bacterial pathogenic toxins, have all been described to punch holes in mitochondria, contributing to cell death processes. Collectively, these findings underscore the vulnerability of mitochondria and the involvement of CL in various pathogenic mechanisms, emphasizing the need for further research on targeting CL-amyloid interactions to mitigate mitochondrial dysfunction.

Keywords:  amyloid proteins; cardiolipin; cytotoxins; membranes; mitochondria; pores

DOI:  https://doi.org/10.1111/jnc.16213
Mitochondrion. 2024 Aug 31. pii: S1567-7249(24)00109-0. [Epub ahead of print]79 101951

Mitochondrial bioenergetics of breast cancer.

Tashvinder Singh, Kangan Sharma, Laxmipriya Jena, Prabhsimran Kaur, Sandeep Singh, Anjana Munshi.

  Breast cancer cells exhibit metabolic heterogeneity based on tumour aggressiveness. Glycolysis and mitochondrial respiration are two major metabolic pathways for ATP production. The oxygen flux, oxygen tension, proton leakage, protonmotive force, inner mitochondrial membrane potential, ECAR and electrochemical proton gradient maintain metabolic homeostasis, ATP production, ROS generation, heat dissipation, and carbon flow and are referred to as "sub-domains" of mitochondrial bioenergetics. Tumour aggressiveness is influenced by these mechanisms, especially when breast cancer cells undergo metastasis. These physiological parameters for healthy mitochondria are as crucial as energy demands for tumour growth and metastasis. The instant energy demands are already elucidated under Warburg effects, while these parameters may have dual functionality to maintain cellular bioenergetics and cellular health. The tumour cell might maintain these mitochondrial parameters for mitochondrial health or avoid apoptosis, while energy production could be a second priority. This review focuses explicitly on the crosstalk between metabolic domains and the utilisation of these parameters by breast cancer cells for their progression. Some major interventions are discussed based on mitochondrial bioenergetics that need further investigation. This review highlights the pathophysiological significance of mitochondrial bioenergetics and the regulation of its sub-domains by breast tumour cells for uncontrolled proliferation.

Keywords:  Breast Cancer; Electron transport chain; Mitochondrial respiration; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.mito.2024.101951
Cell Death Dis. 2024 Aug 27. 15(8): 625

Dopaminergic neurons lacking Caspase-3 avoid apoptosis but undergo necrosis after MPTP treatment inducing a Galectin-3-dependent selective microglial phagocytic response.

Juan García-Revilla, Rocío Ruiz, Ana M Espinosa-Oliva, Marti Santiago, Irene García-Domínguez, Lluís Camprubí-Ferrer, Sara Bachiller, Tomas Deierborg, Bertrand Joseph, Rocío M de Pablos, José A Rodríguez-Gómez, José Luis Venero.

Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc). Apoptosis is thought to play a critical role in the progression of PD, and thus understanding the effects of antiapoptotic strategies is crucial for developing potential therapies. In this study, we developed a unique genetic model to selectively delete Casp3, the gene encoding the apoptotic protein caspase-3, in dopaminergic neurons (TH-C3KO) and investigated its effects in response to a subacute regime of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, which is known to trigger apoptotic loss of SNpc dopaminergic neurons. We found that Casp3 deletion did not protect the dopaminergic system in the long term. Instead, we observed a switch in the cell death pathway from apoptosis in wild-type mice to necrosis in TH-C3KO mice. Notably, we did not find any evidence of necroptosis in our model or in in vitro experiments using primary dopaminergic cultures exposed to 1-methyl-4-phenylpyridinium in the presence of pan-caspase/caspase-8 inhibitors. Furthermore, we detected an exacerbated microglial response in the ventral mesencephalon of TH-C3KO mice in response to MPTP, which mimicked the microglia neurodegenerative phenotype (MGnD). Under these conditions, it was evident the presence of numerous microglial phagocytic cups wrapping around apparently viable dopaminergic cell bodies that were inherently associated with galectin-3 expression. We provide evidence that microglia exhibit phagocytic activity towards both dead and stressed viable dopaminergic neurons through a galectin-3-dependent mechanism. Overall, our findings suggest that inhibiting apoptosis is not a beneficial strategy for treating PD. Instead, targeting galectin-3 and modulating microglial response may be more promising approaches for slowing PD progression.

DOI: https://doi.org/10.1038/s41419-024-07014-9
Med Oncol. 2024 Sep 01. 41(10): 238

How mitochondrial dynamics imbalance affects the progression of breast cancer:a mini review.

Jingwen Kuang, Hao Liu, Linlin Feng, Yuan Xue, Huiyi Tang, Pengcheng Xu.

  Despite the high incidence of breast cancer in women worldwide, there are still great challenges in the treatment process. Mitochondria are highly dynamic organelles, and their dynamics involve cellular energy conversion, signal conduction and other processes. In recent years, an increasing number of studies have affirmed the dynamics of mitochondria as the basis for cancer progression and metastasis; that is, an imbalance between mitochondrial fission and fusion may lead to the progression and metastasis of breast cancer. Here, we review the latest insights into mitochondrial dynamics in the progression of breast cancer and emphasize the clinical value of mitochondrial dynamics in diagnosis and prognosis, as well as important advances in clinical research.

Keywords:  Breast cancer; Mitochondria; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion

DOI:  https://doi.org/10.1007/s12032-024-02479-2