Taxonomy: 2025

Background: Elevated levels of cardiac branched-chain amino acids (BCAAs) and their metabolites, namely branched-chain keto acids (BCKAs), contribute to the development of insulin resistance, contractile dysfunction, and adverse remodeling in the failing heart. However, there is still confusion about whether BCAA or BCKA mediate these detrimental effects in the failing heart.

Methods: Cardiac-specific mitochondrial branched-chain aminotransferase, the enzyme that converts BCAA into BCKA, knockout (BCAT2^–/-) mice underwent a sham or transverse aortic constriction surgery to induce heart failure. Changes in cardiac function and structure were monitored pre- and posttransverse aortic constriction using echocardiography, and metabolic flux through the tricarboxylic acid cycle was measured by perfusing isolated working hearts with radiolabeled energy substrates. Direct effects of BCAA and BCKA on cell hypertrophy were characterized using phenylephrine-induced cell hypertrophy in differentiated cells.

Results: Lowering cardiac BCKA levels in BCAT2^-/- failing hearts increases insulin-stimulated glucose oxidation rates via enhancing mitochondrial protein kinase B and pyruvate dehydrogenase complex activities. Increased glucose oxidation rates in BCAT2^-/- failing hearts enhanced cardiac efficiency by decreasing myocardial oxygen consumption rates. However, cardiac BCAA accumulation was associated with excessive stimulation of the mammalian target of rapamycin signaling and aggravation of adverse cardiac remodeling in BCAT2^-/- failing hearts. As a result, the impact of BCAA accumulation offsets the beneficial effects of lowering cardiac BCKA levels on cardiac insulin sensitivity and cardiac efficiency.

Lipid phosphate phosphatase 3 (LPP3) is a membrane-bound enzyme that hydrolyzes lipid phosphates including the bioactive lipid, lysophosphatidic acid (LPA). Elevated circulating LPA production and cellular LPA signaling are implicated in obesity-induced metabolic and cardiac dysfunction. Deletion of LPP3 in the cardiomyocyte increases circulating LPA levels and causes heart failure and mitochondrial dysfunction in mice. To examine the influence of LPP3 modulation in the cardiomyocyte on obesity-induced cardiomyopathy, we generated mice with cardiomyocyte-specific LPP3 overexpression (LPP3OE mice) driven by the α myosin heavy chain promoter. Female and male control (LPP3FL) and LPP3OE mice were fed low-fat diet (LFD) or high-fat diet (HFD) for up to 22-23 wk, followed by the analysis of glucose homeostasis, cardiac function, plasma LPA levels, and mitochondrial respiration in cardiac myofibers. On LFD, both female and male LPP3OE mice had markedly reduced plasma LPA levels and increased pyruvate-linked respiration when compared with LPP3FL mice while body weight and global insulin sensitivity were similar between genotypes. Following HFD feeding, female LPP3OE mice were protected from increased plasma LPA levels, excess adiposity, systemic insulin resistance, and systolic and diastolic cardiac dysfunction compared with LPP3FL mice. Female LPP3OE mice also maintained elevated cardiac pyruvate-linked mitochondrial respiration following HFD feeding while mitochondrial respiration was similar between genotypes in HFD-fed male mice. This study suggests that cardiomyocyte-specific LPP3 upregulation protects particularly female mice from HFD-induced metabolic dysfunction and cardiomyopathy.NEW & NOTEWORTHY Lipid phosphate phosphatase 3 (LPP3) hydrolyzes bioactive lipids including lysophosphatidic acid (LPA), elevated levels of which are implicated in obesity-induced metabolic and cardiac dysfunction. We show that cardiac-specific overexpression of LPP3 lowers plasma LPA levels, blunts LPA signaling in cardiomyocytes, and increases pyruvate-linked mitochondrial respiration in the heart at baseline in both male and female mice. In female mice, LPP3 overexpression also protects from high-fat diet-induced obesity, insulin resistance, and cardiac dysfunction.

TNBC remains the most aggressive and therapy-resistant type of breast cancer, for which efficient targeted therapies have not been developed yet. Here, we identified TRPML3 (ML3) as a potential therapeutic target in TNBC. Our data showed that ML3 is significantly upregulated in TNBC cells compared with nontumorigenic control cells. ML3 knockdown (KD) impairs TNBC cell proliferation by inducing cell cycle arrest and caspase-dependent apoptosis. ML3 KD also inhibits TNBC cell migration and invasion. Mechanistically, ML3 KD reduces lysosomal number and enhances lysosomal acidification, which in turn activates mTORC1, thereby inhibiting autophagy initiation and flux. This disruption negatively impacts mitochondrial function, as evidenced by reduced ATP production, increased ROS and NO production, and mitochondrial fragmentation. Importantly, ML3 KD enhances TNBC cell sensitivity to doxorubicin and paclitaxel. The finding suggests that targeting ML3 disrupts lysosomal and mitochondrial homeostasis and enhance chemosensitivity, presenting ML3 as a potential therapeutic vulnerability in TNBC enhancing chemosensitivity.

The Marathon of Hope Cancer Centres Network (MOHCCN), led by the Terry Fox Research Institute and the Terry Fox Foundation, unites researchers, clinicians, patients, funders, and other partners across Canada to accelerate precision oncology, promote collaboration and data sharing, and ultimately improve patient outcomes. This overview outlines the Network’s goals, history, and challenges and opportunities. We also highlight progress toward the “MOHCCN Gold Cohort,” a shared resource of clinical and genomic data from 15,000 patients.