bims-medica 2025-01-05 papers

Issue of 2025–01–05
five papers selected by
Brett Chrest, Wake Forest University

mSphere. 2024 Dec 31. e0088324

A thermodynamic bottleneck in the TCA cycle contributes to acetate overflow in Staphylococcus aureus.

Nabia Shahreen, Jongsam Ahn, Adil Alsiyabi, Niaz Bahar Chowdhury, Dhananjay Shinde, Sujata S Chaudhari, Kenneth W Bayles, Vinai C Thomas, Rajib Saha.

During aerobic growth, S. aureus relies on acetate overflow metabolism, a process where glucose is incompletely oxidized to acetate, for its bioenergetic needs. Acetate is not immediately captured as a carbon source and is excreted as waste by cells. The underlying factors governing acetate overflow in S. aureus have not been identified. Here, we show that acetate overflow is favored due to a thermodynamic bottleneck in the TCA cycle specifically involving the oxidation of succinate to fumarate by succinate dehydrogenase. This bottleneck reduces flux through the TCA cycle, making it more efficient for S. aureus to generate ATP via acetate overflow metabolism. Additionally, the protein allocation cost of maintaining ATP flux through the restricted TCA cycle is greater than that of acetate overflow metabolism. Finally, we show that the TCA cycle bottleneck provides S. aureus the flexibility to redirect carbon toward maintaining redox balance through lactate overflow when oxygen becomes limiting, albeit at the expense of ATP production through acetate overflow. Overall, our findings suggest that overflow metabolism offers S. aureus distinct bioenergetic advantages over a thermodynamically constrained TCA cycle, potentially supporting its commensal-pathogenic lifestyle.

Keywords: acetate overflow; membrane crowding; overflow metabolism; redox imbalance; thermodynamic bottleneck

DOI: https://doi.org/10.1128/msphere.00883-24

Front Biosci (Landmark Ed). 2024 Nov 27. 29(12): 402

The Warburg Effect: Is it Always an Enemy?

Christos Papaneophytou.

The Warburg effect, also known as 'aerobic' glycolysis, describes the preference of cancer cells to favor glycolysis over oxidative phosphorylation for energy (adenosine triphosphate-ATP) production, despite having high amounts of oxygen and fully active mitochondria, a phenomenon first identified by Otto Warburg. This metabolic pathway is traditionally viewed as a hallmark of cancer, supporting rapid growth and proliferation by supplying energy and biosynthetic precursors. However, emerging research indicates that the Warburg effect is not just a strategy for cancer cells to proliferate at higher rates compared to normal cells; thus, it should not be considered an 'enemy' since it also plays complex roles in normal cellular functions and/or under stress conditions, prompting a reconsideration of its purely detrimental characterization. Moreover, this review highlights that distinguishing glycolysis as 'aerobic' and 'anaerobic' should not exist, as lactate is likely the final product of glycolysis, regardless of the presence of oxygen. Finally, this review explores the nuanced contributions of the Warburg effect beyond oncology, including its regulatory roles in various cellular environments and the potential effects on systemic physiological processes. By expanding our understanding of these mechanisms, we can uncover novel therapeutic strategies that target metabolic reprogramming, offering new avenues for treating cancer and other diseases characterized by metabolic dysregulation. This comprehensive reevaluation not only challenges traditional views but also enhances our understanding of cellular metabolism's adaptability and its implications in health and disease.

Keywords: Warburg effect; cancer metabolism; cellular metabolism; glycolysis; metabolic reprogramming

DOI: https://doi.org/10.31083/j.fbl2912402

Sci Adv. 2025 Jan 03. 11(1): eads8489

Somatic mtDNA mutation burden shapes metabolic plasticity in leukemogenesis.

Xiujie Li-Harms, Jingjun Lu, Yu Fukuda, John Lynch, Aditya Sheth, Gautam Pareek, Marcin M Kaminski, Hailey S Ross, Christopher W Wright, Amber L Smith, Huiyun Wu, Yong-Dong Wang, Marc Valentine, Geoffrey Neale, Peter Vogel, Stanley Pounds, John D Schuetz, Min Ni, Mondira Kundu.

The role of somatic mitochondrial DNA (mtDNA) mutations in leukemogenesis remains poorly characterized. To determine the impact of somatic mtDNA mutations on this process, we assessed the leukemogenic potential of hematopoietic progenitor cells (HPCs) from mtDNA mutator mice (Polg D257A) with or without NMyc overexpression. We observed a higher incidence of spontaneous leukemogenesis in recipients transplanted with heterozygous Polg HPCs and a lower incidence of NMyc-driven leukemia in those with homozygous Polg HPCs compared to controls. Although mtDNA mutations in heterozygous and homozygous HPCs caused similar baseline impairments in mitochondrial function, only heterozygous HPCs responded to and supported altered metabolic demands associated with NMyc overexpression. Homozygous HPCs showed altered glucose utilization with pyruvate dehydrogenase inhibition due to increased phosphorylation, exacerbated by NMyc overexpression. The impaired growth of NMyc-expressing homozygous HPCs was partially rescued by inhibiting pyruvate dehydrogenase kinase, highlighting a relationship between mtDNA mutation burden and metabolic plasticity in leukemogenesis.

DOI: https://doi.org/10.1126/sciadv.ads8489

Curr Opin Cell Biol. 2024 Dec 29. pii: S0955-0674(24)00139-X. [Epub ahead of print]92 102460

Beyond static snapshots: Mitochondria in action.

Julien Cicero, Uri Manor.

Mitochondria are dynamic organelles essential for cellular homeostasis, undergoing continuous fission and fusion processes that regulate their morphology, distribution, and function. Disruptions in these dynamics are linked to numerous diseases, including neurodegenerative disorders and cancer. Understanding these processes is vital for developing therapeutic strategies aimed at mitigating mitochondrial dysfunction. This review provides an overview of recent perspectives on mitochondrial dynamics, focusing on the need for live video microscopy imaging in order to fully understand mitochondrial phenotypes and pathology. Advanced imaging tools, such as machine learning-based segmentation and label-free microscopy approaches, have the potential to transform our ability to study mitochondrial dynamics in live cells.

DOI: https://doi.org/10.1016/j.ceb.2024.102460

Nutr Metab Cardiovasc Dis. 2024 Nov 23. pii: S0939-4753(24)00439-3. [Epub ahead of print] 103805

Is isocaloric intermittent fasting superior to calorie restriction? A systematic review and meta-analysis of RCTs.

Mohammed Hamsho, Wijdan Shkorfu, Yazan Ranneh, Abdulmannan Fadel.

BACKGROUND AND AIM: Intermittent fasting (IF) has been demonstrated to enhance human health through several mechanisms. However, it is still unclear whether those health benefits are independent of caloric restriction (CR)-induced weight loss. This systematic review and meta-analysis aimed to compare isocaloric IF and CR regarding anthropometric measurements, adherence, metabolic profile, inflammatory biomarkers, and adipokines in adults and elderlies.
METHODS AND RESULTS: Comprehensive research was conducted usin four major databases including Embase, PubMed, Scopus, and Google Scholar without date restriction. Mean differences of the change from baseline ± change SD were calculated as the differences between IF and CR groups. Subgroup analysis was performed according to intervention duration (short-, medium-, and long-term). To determine the reliability of our findings, GRADE assessment was performed. As a result, 20 RCTs were included in this systematic review and meta-analysis. IF groups had significant reductions in fat mass (kg) (P = 0.006) and Interleukin-6 (P < 0.00001) in the short term and fat mass (%) (P = 0.0002), waist circumference (P = 0.005), fasting blood insulin (P < 0.00001) and HOMA-IR (P = 0.04) in the long term. CR groups had significantly lower hunger (P = 0.003), fatigue (P = 0.04), and TG (P = 0.03).
CONCLUSIONS: IF may be an effective alternative to CR but is not superior to CR in enhancing human health. Due to the low number of long-term studies, future studies should focus on conducting longitudinal randomized trials comparing IF and CR in different populations, age groups, and IF patterns.

Keywords: Adherence; Anthropometric measurements; Caloric restriction; GRADE; Intermittent fasting; Isocaloric; Meta-analysis; Metabolic profile

DOI: https://doi.org/10.1016/j.numecd.2024.103805