bims-mimbat 2025-06-22 papers

Redox Biol. 2025 Jun 09. pii: S2213-2317(25)00228-9. [Epub ahead of print]85 103715

Regulation of redox homeostasis by ATF4-MTHFD2 axis during white adipose tissue browning.

Rehna Paula Ginting, Hoang-Anh Pham-Bui, Choijamts Munkhzul, Siti Aisyah Fuad, Ahyeon Son, Jong-Seok Moon, Jaeseok Han, Mihye Lee, Min-Woo Lee.

Maintaining redox balance is crucial for mitochondrial homeostasis. During browning of white adipocytes, both the quality and quantity of mitochondria undergo dramatic changes. However, the mechanisms controlling the redox balance in the mitochondria during this process remain unclear. In this study, we demonstrate that thermogenic activation occurs before mitochondrial biogenesis during cold-induced browning of inguinal white adipose tissue (iWAT) and is accompanied by increased mitochondrial stress and integrated stress response (ISR) signaling. Specifically, cold exposure enhances the expression of ATF4, an ISR effector. Adipocyte-specific deletion of ATF4 results in increased energy expenditure, but paradoxically leads to a lower core body temperature, and heightened pro-inflammation in iWAT after cold exposure, which is restored by the antioxidant, MitoQ. Mechanistically, ATF4 regulates the redox balance through MTHFD2, an enzyme involved in mitochondrial redox homeostasis by NADPH generation. Cold exposure upregulates MTHFD2 expression in an ATF4-dependent manner, and its inhibition by DS18561882 in vivo leads to impaired cold-induced mitochondrial respiration similar to the effects of ATF4 loss. These findings suggest that ATF4 is essential for redox balance via MTHFD2, thereby affecting tissue homeostasis during iWAT browning.

DOI: https://doi.org/10.1016/j.redox.2025.103715

Nat Struct Mol Biol. 2025 Jun 19.

ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism.

Edrees H Rashan, Abigail K Bartlett, Daven B Khana, Jingying Zhang, Raghav Jain, Gina Wade, Luciano A Abriata, Andrew J Smith, Zakery N Baker, Taylor Cook, Alana Caldwell, Autumn R Chevalier, Patrick Forny, Brian F Pfleger, Matteo Dal Peraro, Peng Yuan, Daniel Amador-Noguez, Judith A Simcox, David J Pagliarini.

Fatty acid β-oxidation is a central catabolic pathway with broad health implications. However, various fatty acids, including 4-hydroxy acids (4-HAs), are largely incompatible with β-oxidation machinery before being modified. Here we reveal that two atypical acyl-CoA dehydrogenases, ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains that phosphorylate the 4-hydroxy position as a requisite step in converting 4-hydroxyacyl-CoAs into conventional 2-enoyl-CoAs. Through cryo-electron microscopy and molecular modeling, we identified an atypical dehydrogenase binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain 4-HAs, whereas ACAD11 is peroxisomal and enables longer-chain 4-HA catabolism. Mice lacking ACAD11 accumulate 4-HAs in their plasma and females are susceptible to body weight and fat gain, concurrent with decreased adipocyte differentiation and adipokine expression. Collectively, we present that ACAD10 and ACAD11 are the primary gatekeepers of mammalian 4-HA catabolism.

DOI: https://doi.org/10.1038/s41594-025-01596-4

J Biol Chem. 2025 Jun 11. pii: S0021-9258(25)02211-2. [Epub ahead of print] 110361

Proton gradient controls the lateral rearrangement of inner membrane domains in response to membrane fluidizer stress in Mycobacterium smegmatis.

Malavika Prithviraj, F N U Shivangi, Joel S Freundlich, Yasu S Morita.

Mycobacterium smegmatis partitions its plasma membrane into two distinct regions: the inner membrane domain (IMD) and the conventional plasma membrane. IMD, enriched in the sub-polar regions of actively growing rod-shaped cell, contains many membrane proteins involved in cell envelope biosynthesis. Dibucaine, a membrane fluidizer, disrupts plasma membrane integrity and de-partitions the IMD from the sub-polar regions. We do not know what governs the de-partitioning of the IMD in response to dibucaine stress. In this study, we investigated the stress response of the IMD under respiration defect. We first depleted MenG, a key enzyme in the menaquinone biosynthesis, by CRISPRi and observed that the IMD does not respond to dibucaine-induced membrane stress. CRISPRi-induced knockdown of qcrC, a gene encoding a component of an electron transport chain cytochrome, corroborated the results of menG knockdown. In contrast, neither CRISPRi knockdown of atpD, a gene encoding a component of the ATP synthase nor inhibition of ATP synthase by bedaquiline inhibited the dibucaine-induced de-partitioning of sub-polar IMD as robustly as CRISPRi knockdowns of menG and qcrC. A pretreatment with the protonophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP) prevented dibucaine-induced IMD de-partitioning. Furthermore, a pretreatment with nigericin, which acts as a H+/K+ antiporter and disrupts the proton gradient without affecting membrane potential, also inhibited the IMD de-partitioning in a way similar to CCCP. Taken together, our findings suggest that membrane stress-induced IMD delocalization is not a passive lipid dispersion but an active membrane rearrangement dependent on an electrochemical gradient of proton.

Keywords: Mycobacterium; membrane fluidity; plasma membrane; proton motive force; stress response

DOI: https://doi.org/10.1016/j.jbc.2025.110361

Am J Physiol Endocrinol Metab. 2025 Jun 16.

Non-equilibrium Thermodynamic Analysis of Human Bioenergetics in Obesity: Implications of the Second Law.

Nawfal Istfan.

The fundamental principle of energy balance, a statement of the first law of thermodynamics, overlooks the second law, resulting in gaps in our knowledge of body weight regulation and obesity. This study develops research tools to implement non-equilibrium thermodynamics in human subjects based on a mitochondrial energy conversion model. A key advancement measures ATP phosphorylation through its relationship to the mitochondrial redox couple, beta-hydroxybutyrate, and acetoacetate. Applying this methodology in humans, utilizing data from a recent study, provides a comprehensive understanding of the impact of the second law. The results demonstrate that oxidative phosphorylation efficiency is approximately 57%, with minor but significant variations among individuals. Four out of 24 healthy subjects exhibited sufficiently higher efficiency of oxidative phosphorylation and lower free energy dissipation compared to the remaining subjects. Feeding is associated with lower efficiency, a higher rate of free energy dissipation, and a slight reduction in coupling. The amount of energy utilized for useful work represents only one-third of resting energy expenditure. These findings are integrated with the current principle of energy balance to adhere to the constraints of the first and second laws. Based on theoretical modeling, it is demonstrated that inter-individual differences and variations in mitochondrial efficiency and energy dissipation during specific metabolic conditions can lead to discrepancies between total energy balance and the balance of the fraction of energy used for useful work. Consequently, the constraints imposed by the second law should be incorporated into the current understanding of energy balance and obesity.

Keywords: entropy production; metabolic efficiency; second law of thermodynamics; total energy expenditure

DOI: https://doi.org/10.1152/ajpendo.00487.2024