bims-miptne 2024-07-28 papers

JCI Insight. 2024 Jul 25. pii: e180906. [Epub ahead of print]

Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.

Joseph R Visker, Ahmad A Cluntun, Jesse N Velasco-Silva, David R Eberhardt, Luis Cedeno-Rosario, Thirupura S Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, J Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S Ducker, Stavros G Drakos, Jared Rutter.

The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart, however the rapid re-introduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the final myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and re-directing pyruvate towards oxidation can blunt hypertrophy. We hypothesized this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. Post-I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψ), and Ca2+, increased pyruvate entry to TCA cycle, increased oxygen consumption, improved myocardial salvage and functional outcomes following I/R. Our data suggests normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.

Keywords: Carbohydrate metabolism; Cardiology; Cardiovascular disease; Metabolism; Mitochondria

DOI: https://doi.org/10.1172/jci.insight.180906

Nat Commun. 2024 Jul 21. 15(1): 6143

ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.

Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health.

DOI: https://doi.org/10.1038/s41467-024-50502-x

Cells. 2024 Jul 10. pii: 1177. [Epub ahead of print]13(14):

The Multiple Roles of Lactate in the Skeletal Muscle.

Bianca Bartoloni, Michele Mannelli, Tania Gamberi, Tania Fiaschi.

Believed for a long time to be merely a waste product of cell metabolism, lactate is now considered a molecule with several roles, having metabolic and signalling functions together with a new, recently discovered role as an epigenetic modulator. Lactate produced by the skeletal muscle during physical exercise is conducted to the liver, which uses the metabolite as a gluconeogenic precursor, thus generating the well-known "Cori cycle". Moreover, the presence of lactate in the mitochondria associated with the lactate oxidation complex has become increasingly clear over the years. The signalling role of lactate occurs through binding with the GPR81 receptor, which triggers the typical signalling cascade of the G-protein-coupled receptors. Recently, it has been demonstrated that lactate regulates chromatin state and gene transcription by binding to histones. This review aims to describe the different roles of lactate in skeletal muscle, in both healthy and pathological conditions, and to highlight how lactate can influence muscle regeneration by acting directly on satellite cells.

Keywords: GPR81 receptor; lactate; muscle renewal

DOI: https://doi.org/10.3390/cells13141177

Mol Cell Biochem. 2024 Jul 20.

Mitochondrial complex-1 as a therapeutic target for cardiac diseases.

Neeraj Kumar Rai, Harikrishnan Venugopal, Rithika Rajesh, Pranavi Ancha, Sundararajan Venkatesh.

Mitochondrial dysfunction is critical for the development and progression of cardiovascular diseases (CVDs). Complex-1 (CI) is an essential component of the mitochondrial electron transport chain that participates in oxidative phosphorylation and energy production. CI is the largest multisubunit complex (~ 1 Mda) and comprises 45 protein subunits encoded by seven mt-DNA genes and 38 nuclear genes. These subunits function as the enzyme nicotinamide adenine dinucleotide hydrogen (NADH): ubiquinone oxidoreductase. CI dysregulation has been implicated in various CVDs, including heart failure, ischemic heart disease, pressure overload, hypertrophy, and cardiomyopathy. Several studies demonstrated that impaired CI function contributes to increased oxidative stress, altered calcium homeostasis, and mitochondrial DNA damage in cardiac cells, leading to cardiomyocyte dysfunction and apoptosis. CI dysfunction has been associated with endothelial dysfunction, inflammation, and vascular remodeling, critical processes in developing atherosclerosis and hypertension. Although CI is crucial in physiological and pathological conditions, no potential therapeutics targeting CI are available to treat CVDs. We believe that a lack of understanding of CI's precise mechanisms and contributions to CVDs limits the development of therapeutic strategies. In this review, we comprehensively analyze the role of CI in cardiovascular health and disease to shed light on its potential therapeutic target role in CVDs.

Keywords: Cardiac diseases; Complex I; Heart failure; Mitochondrial dysfunction; Reactive oxygen species

DOI: https://doi.org/10.1007/s11010-024-05074-1

Cells. 2024 Jul 15. pii: 1193. [Epub ahead of print]13(14):

Peptide Blockers of PD-1-PD-L1 Interaction Reinvigorate PD-1-Suppressed T Cells and Curb Tumor Growth in Mice.

Shanshan Jenny Zhong, Xiaoling Liu, Tomonori Kaneko, Yan Feng, Owen Hovey, Kyle Yang, Sally Ezra, Soon-Duck Ha, Sung Kim, John K McCormick, Huadong Liu, Shawn Shun-Cheng Li.

The programmed cell death protein 1 (PD-1) plays a critical role in cancer immune evasion. Blocking the PD-1-PD-L1 interaction by monoclonal antibodies has shown remarkable clinical efficacy in treating certain types of cancer. However, antibodies are costly to produce, and antibody-based therapies can cause immune-related adverse events. To address the limitations associated with current PD-1/PD-L1 blockade immunotherapy, we aimed to develop peptide-based inhibitors of the PD-1/PD-L1 interaction as an alternative means to PD-1/PD-L1 blockade antibodies for anti-cancer immunotherapy. Through the functional screening of peptide arrays encompassing the ectodomains of PD-1 and PD-L1, followed by the optimization of the hit peptides for solubility and stability, we have identified a 16-mer peptide, named mL7N, with a remarkable efficacy in blocking the PD-1/PD-L1 interaction both in vitro and in vivo. The mL7N peptide effectively rejuvenated PD-1-suppressed T cells in multiple cellular systems designed to recapitulate the PD-1/PD-L1 interaction in the context of T-cell receptor signaling. Furthermore, PA-mL7N, a chimera of the mL7N peptide coupled to albumin-binding palmitic acid (PA), significantly promoted breast cancer cell killing by peripheral blood mononuclear cells ex vivo and significantly curbed tumor growth in a syngeneic mouse model of breast cancer. Our work raises the prospect that mL7N may serve as a prototype for the development of a new line of peptide-based immunomodulators targeting the PD-1/PD-L1 immune checkpoint with potential applications in cancer treatment.

Keywords: PD-1 ligand-1 (PD-L1); PD-1/PD-L1 blocking peptide; immune checkpoint blockade; peptide-based immunomodulator; programmed cell death-1 (PD-1)

DOI: https://doi.org/10.3390/cells13141193