Biology subjects

Kukurugya, M. A.

Publications and source records attributed to Kukurugya, M. A..

3 recordsLinked to original sources

bioRxiv2023

Effects of aging on glucose and lipid metabolism in mice

Aging is accompanied by multiple molecular changes that contribute to aging-associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part because mitochondria are central to cellular metabolism. Moreover, the co-factor NAD+, which is reported to decline across multiple tissue types during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and Diversity Outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of up-regulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. Because mitochondrial respiration, a major source of NAD+ regeneration, is reported to decline with age, our data supports a model where NAD+-generating lipid metabolism reactions may buffer against changes in NAD+/NADH during healthy aging.

physiology↗

bioRxiv2022

The Warburg Effect is the result of faster ATP production by glycolysis than respiration

Many prokaryotic and eukaryotic cells metabolize glucose to organism-specific byproducts instead of fully oxidizing it to carbon dioxide and water-a phenomenon referred to as the Warburg Effect. The benefit to a cell has been unclear, given that partial metabolism of glucose yields an order of magnitude less ATP per molecule of glucose than complete oxidation. We show that glycolysis produces ATP faster per gram of pathway protein than respiration in E. coli, S. cerevisiae, and mammalian cells. A simple mathematical model that uses yield, rate, and proteome occupancy of glycolysis and respiration as the only parameters accurately predicts absolute rates of glycolysis and respiration in all three organisms under diverse conditions. Our study suggests that the Warburg Effect is a consequence of the optimization of the rate of energy generation under the constraint of finite proteome space. One-Sentence SummaryThe Warburg Effect is a manifestation by which cells across kingdoms of life optimize the rate of energy production.

systems biology↗

bioRxiv2022

Impairment of lipid homoeostasis causes accumulation of protein aggregates in the lysosome

Protein aggregation increases during aging and is a pathological hallmark of many age-related diseases. Protein homeostasis (proteostasis) depends on a core network of factors directly influencing protein production, folding, trafficking, and degradation. Cellular proteostasis also depends on the overall composition of the proteome and numerous environmental variables. Modulating this cellular proteostasis state can influence the stability of multiple endogenous proteins, yet the factors contributing to this state remain incompletely characterized. Here, we performed genome-wide CRISPRi screens to elucidate the modulators of proteostasis state in mammalian cells, using a fluorescent dye to monitor endogenous protein aggregation. These screens identified known components of the proteostasis network and uncovered a novel link between protein and lipid homeostasis. Increasing lipid uptake and/or disrupting lipid metabolism promotes the accumulation of sphingomyelins and cholesterol esters and drives the formation of detergent-insoluble protein aggregates at the lysosome. Proteome profiling of lysosomes revealed ESCRT accumulation, suggesting disruption of ESCRT disassembly, lysosomal membrane repair, and microautophagy. Lipid dysregulation leads to lysosomal membrane permeabilization but does not otherwise impact fundamental aspects of lysosomal and proteasomal functions. Together, these results demonstrate that lipid dysregulation disrupts ESCRT function and impairs proteostasis.

cell biology↗