Biology subjects

Queliconi, B. B.

Publications and source records attributed to Queliconi, B. B..

3 recordsLinked to original sources

bioRxiv2026

Branched-chain amino acid fermentation as an alternative mammalian electron sink

Hypoxia disrupts mitochondrial respiration and increases the NADH/NAD+ ratio, causing reductive stress. To maintain redox homeostasis, mammalian cells divert electrons toward fermentation. While fermentation in mammals typically involves lactate production, we identify the fermentation of branched-chain amino acids (BCAAs) as an alternative electron sink activated by hypoxia. The resulting metabolites are excreted in urine as a distinct mechanism for alleviating reductive stress. BCAA fermentation is catalyzed by lactate dehydrogenase (LDH) enzymes and is highly responsive to the NADH/NAD+ ratio. Consequently, BCAA fermentation products are sensitive biomarkers for reductive stress in human contexts ranging from resistance exercise to severe hypoxemia. Furthermore, we find that mouse sperm have evolved highly efficient BCAA fermentation, providing a specific metabolic strategy to support the anaerobic electron flow that facilitates flagellar hypermotility across mammalian sperm. Our work highlights an under-appreciated fate of BCAAs in response to reductive stress.

cell biology↗

bioRxiv2023

Cardiac Troponin I Directly Binds and Inhibits Mitochondrial ATP Synthase: a Noncanonical Role in the Post-Ischemic Heart

Cardiac troponin I (cTnI) is a sarcomeric protein critical to myocyte contraction. Unexpectedly, we found that some cTnI localized to the mitochondrial matrix in the heart, inhibited mitochondrial functions when stably expressed in non-cardiac cells and increased opening of the mitochondrial permeability transition pore under oxidative stress. Direct, specific, and saturable binding of cTnI to ATP synthase was demonstrated in vitro, using immune-captured ATP synthase, and in cells using proximity ligation assay. cTnI binding doubled F1F0 ATPase activity, whereas skeletal troponin I and several human mutant cTnI variants associated with familial hypertrophic cardiomyopathy did not. A rationally-designed ten amino acid peptide, P888, inhibited cTnI binding to ATP synthase, inhibited cTnI-induced increase in ATPase activity in vitro, and reduced cardiac injury following transient ischemia in vivo. We therefore suggest that mitochondria-associated cTnI may inhibit cardiac ATP synthase under basal conditions; pharmacological agents that release this inactivating effect of cTnI and thus preventing ATP hydrolysis during cardiac ischemia may increase the reservoir of functional mitochondria to reduce cardiac injury. Significance StatementCardiac troponin I (cTnI) is a key sarcomeric protein involved in the regulation of myocardial contractility. We found that some cTnI is present in the mitochondrial matrix where it binds to ATP synthase, disrupting mitochondrial function; inhibition of the cTnI-ATP synthase interaction with a selective peptide inhibitor reduces cardiac dysfunction following ischemia and reperfusion injury. Several pathogenic cTnI mutations associated with hypertrophic cardiomyopathy do not affect ATP synthase activity, suggesting a potential mechanism that contributes to the diverse pathologies associated with these mutations.

cell biology↗

bioRxiv2022

Organ-Specific Fuel Rewiring in Acute and Chronic Hypoxia Redistributes Glucose and Fatty Acid Metabolism

Oxygen deprivation can be detrimental. However, chronic hypoxia is associated with decreased incidence of metabolic syndrome and cardiovascular disease in high-altitude populations. Previously, hypoxic fuel rewiring has primarily been studied in immortalized cells. Here, we describe how systemic hypoxia rewires fuel metabolism to optimize whole-body adaptation. Acclimatization to hypoxia coincided with dramatically lower blood glucose and adiposity. Using in vivo fuel uptake and flux measurements, we found that organs partitioned fuels differently during hypoxia adaption. Acutely, most organs increased glucose uptake and suppressed aerobic glucose oxidation, consistent with previous in vitro investigations. In contrast, brown adipose tissue and skeletal muscle became "glucose savers," suppressing glucose uptake by 3-5-fold. Interestingly, chronic hypoxia produced distinct patterns: the heart relied increasingly on glucose oxidation, and unexpectedly, the brain, kidney, and liver increased fatty acid uptake and oxidation. Hypoxia-induced metabolic plasticity carries therapeutic implications for chronic metabolic diseases and acute hypoxic injuries.

physiology↗