bims-miptne 2024-08-04 papers

Front Mol Med. 2023 ;3 1235188

Mitochondrial calcium signaling and redox homeostasis in cardiac health and disease.

Tudor-Alexandru Popoiu, Christoph Maack, Edoardo Bertero.

The energy demand of cardiomyocytes changes continuously in response to variations in cardiac workload. Cardiac excitation-contraction coupling is fueled primarily by adenosine triphosphate (ATP) production by oxidative phosphorylation in mitochondria. The rate of mitochondrial oxidative metabolism is matched to the rate of ATP consumption in the cytosol by the parallel activation of oxidative phosphorylation by calcium (Ca2+) and adenosine diphosphate (ADP). During cardiac workload transitions, Ca2+ accumulates in the mitochondrial matrix, where it stimulates the activity of the tricarboxylic acid cycle. In this review, we describe how mitochondria internalize and extrude Ca2+, the relevance of this process for ATP production and redox homeostasis in the healthy heart, and how derangements in ion handling cause mitochondrial and cardiomyocyte dysfunction in heart failure.

Keywords: calcium; cardiomyocyte; heart failure; mitochondria; reactive oxygen species; redox homeostasis

DOI: https://doi.org/10.3389/fmmed.2023.1235188

Redox Biol. 2024 Jul 26. pii: S2213-2317(24)00266-0. [Epub ahead of print]75 103288

Redox-active vitamin C suppresses human osteosarcoma growth by triggering intracellular ROS-iron-calcium signaling crosstalk and mitochondrial dysfunction.

Prajakta Vaishampayan, Yool Lee.

Pharmacological vitamin C (VC) has gained attention for its pro-oxidant characteristics and selective ability to induce cancer cell death. However, defining its role in cancer has been challenging due to its complex redox properties. In this study, using a human osteosarcoma (OS) model, we show that the redox-active property of VC is critical for inducing non-apoptotic cancer cell death via intracellular reactive oxygen species (ROS)-iron-calcium crosstalk and mitochondrial dysfunction. In both 2D and 3D OS cell culture models, only the oxidizable form of VC demonstrated potent dose-dependent cytotoxicity, while non-oxidizable and oxidized VC derivatives had minimal effects. Live-cell imaging showed that only oxidizable VC caused a surge in cytotoxic ROS, dependent on iron rather than copper. Inhibitors of ferroptosis, a form of iron-dependent cell death, along with classical apoptosis inhibitors, were unable to completely counteract the cytotoxic effects induced by VC. Further pharmacological and genetic inhibition analyses showed that VC triggers calcium release through inositol 1,4,5-trisphosphate receptors (IP3Rs), leading to mitochondrial ROS production and eventual cell death. RNA sequencing revealed down-regulation of genes involved in the mitochondrial electron transport chain and oxidative phosphorylation upon pharmacological VC treatment. Consistently, high-dose VC reduced mitochondrial membrane potential, oxidative phosphorylation, and ATP levels, with ATP reconstitution rescuing VC-induced cytotoxicity. In vivo OS xenograft studies demonstrated reduced tumor growth with high-dose VC administration, concomitant with the altered expression of mitochondrial ATP synthase (MT-ATP). These findings emphasize VC's potential clinical utility in osteosarcoma treatment by inducing mitochondrial metabolic dysfunction through a vicious intracellular ROS-iron-calcium cycle.

Keywords: ATP; Electron transport chain; Endoplasmic reticulum oxidoreductase 1 alpha; Inositol 1,4,5-trisphosphate receptors oxidative phosphorylation; Mitochondrial dysfunction; Osteosarcoma; Reactive oxygen species

DOI: https://doi.org/10.1016/j.redox.2024.103288

Cell Death Discov. 2024 Aug 01. 10(1): 346

The endoplasmic reticulum pool of Bcl-xL prevents cell death through IP3R-dependent calcium release.

Rudy Gadet, Lea Jabbour, Trang Thi Minh Nguyen, Olivier Lohez, Ivan Mikaelian, Philippe Gonzalo, Tomas Luyten, Mounira Chalabi-Dchar, Anne Wierinckx, Olivier Marcillat, Geert Bultynck, Ruth Rimokh, Nikolay Popgeorgiev, Germain Gillet.

Apoptosis plays a role in cell homeostasis in both normal development and disease. Bcl-xL, a member of the Bcl-2 family of proteins, regulates the intrinsic mitochondrial pathway of apoptosis. It is overexpressed in several cancers. Bcl-xL has a dual subcellular localisation and is found at the mitochondria as well as the endoplasmic reticulum (ER). However, the biological significance of its ER localisation is unclear. In order to decipher the functional contributions of the mitochondrial and reticular pools of Bcl-xL, we generated genetically modified mice expressing exclusively Bcl-xL at the ER, referred to as ER-xL, or the mitochondria, referred to as Mt-xL. By performing cell death assays, we demonstrated that ER-xL MEFs show increased vulnerability to apoptotic stimuli but are more resistant to ER stress. Furthermore, ER-xL MEFs displayed reduced 1,4,5-inositol trisphosphate receptor (IP3R)-mediated ER calcium release downstream of Phospholipase C activation. Collectively, our data indicate that upon ER stress, Bcl-xL negatively regulates IP3R-mediated calcium flux from the ER, which prevents ER calcium depletion and maintains the UPR and subsequent cell death in check. This work reveals a moonlighting function of Bcl-xL at the level of the ER, in addition to its well-known role in regulating apoptosis through the mitochondria.

DOI: https://doi.org/10.1038/s41420-024-02112-1

Am J Pathol. 2024 Jul 26. pii: S0002-9440(24)00247-5. [Epub ahead of print]

Lactate contributes to remote ischemic preconditioning-mediated protection against myocardial ischemia reperfusion injury by facilitating autophagy via AMPK-mTOR-TFEB-CX43 axis.

Zhang-Jian Yang, Wei-Fang Zhang, Qing-Qing Jin, Zhi-Rong Wu, Yun-Yan Du, Hao Shi, Zhen-Sheng Qu, Xiao-Jian Han, Li-Ping Jiang.

Remote ischemic preconditioning (RIPC) exerts a protective role on myocardial ischemia reperfusion (I/R) injury by the release of various humoral factors. Lactate is a common metabolite in ischemic tissues. Nevertheless, little is known about the role lactate plays in myocardial I/R injury and its underlying mechanism. This investigation revealed that RIPC elevated the level of lactate in blood and myocardium. Furthermore, AZD3965, a selective monocarboxylate transporter 1 (MCT1) inhibitor and 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, mitigated the effects of RIPC-induced elevated lactate in the myocardium and prevented RIPC against myocardial I/R injury. In an in vitro hypoxia reoxygenation (H/R) model, lactate markedly mitigated H/R-induced cell damage in H9c2 cells. Meanwhile, further studies suggested that lactate contributed to RIPC rescuing I/R-induced autophagy deficiency by promoting TFEB translocation to the nucleus through activating the AMPK-mTOR pathway without influencing the PI3K-Akt pathway, thus reducing cardiomyocytes damage. Interestingly, we also found that lactate upregulated the mRNA and protein expression of CX43 by facilitating the binding of TFEB to CX43 promoter in the myocardium. Functionally, silencing of TFEB attenuated the protective effect of lactate on cell damage, which was reversed by overexpression of CX43. Further mechanistic studies suggested lactate facilitated CX43-regulated autophagy via AMPK-mTOR-TFEB signaling pathway. Collectively, our research demonstrates that RIPC protects against myocardial I/R injury through lactate-mediated myocardial autophagy via AMPK-mTOR-TFEB-CX43 axis.

Keywords: autophagy; connexin 43; lactate; myocardial ischemia reperfusion injury; remote ischemic preconditioning

DOI: https://doi.org/10.1016/j.ajpath.2024.07.005