bims-smemid 2026-08-02 papers

bioRxiv. 2026 Jul 17. pii: 2026.07.16.738975. [Epub ahead of print]

The Disease Gene THAP12 is a Transcriptional Regulator of Mitochondrial ETC Complex I.

Brandon R Desousa, Yohei Abe, Martin Kampmann, Isha H Jain.

Complex I (CI) is the largest and most disease-associated component of the mitochondrial electron transport chain. While many diseases are linked to defects in specific CI subunits, the extent to which non-mitochondrial proteins contribute to CI function or disease is less clear. Here, we perform genome-wide CRISPR screens to identify regulators of CI abundance across its N, Q, and P modules, which mediate NADH oxidation, quinone reduction, and proton pumping, respectively. These screens identify THAP12 as a previously unrecognized transcriptional regulator of CI biogenesis. THAP12 loss selectively destabilizes CI and impairs oxidative ATP production. Mechanistically, THAP12 functions in the nucleus as a DNA-binding factor that directly activates genes required for CI assembly and iron-sulfur cluster maintenance, including NDUFAF3, NDUFAF4 and BOLA3. Patient-derived fibroblasts carrying THAP12 mutations exhibit conserved transcriptional defects and profound CI deficiency, establishing THAP12-associated neurodevelopmental disorder as a secondary mitochondrial CI disease. Finally, hypoxia rescues growth defects in THAP12-deficient cells, nominating low-oxygen therapy as a potential treatment strategy. Together, these findings identify THAP12 as a dedicated regulator of CI assembly and expand the genetic landscape of CI disease.

DOI: https://doi.org/10.64898/2026.07.16.738975

bioRxiv. 2026 Jul 20. pii: 2026.07.17.739092. [Epub ahead of print]

Double-bond geometry determines fatty acid metabolic fate and ferroptosis sensitivity.

Cynthia A Harris, Shunji Kato, Yurika Otoki, Elisa Martin Perez, Dylan Boone, Juan Lorenzo B Pablo, Anna Greka, James A Olzmann.

Ferroptosis is driven by the accumulation of oxidatively damaged membrane phospholipids, making membrane lipid composition a central determinant of cell death sensitivity. While fatty acid chain length and degree of unsaturation are well-established regulators of ferroptosis, whether fatty acid stereochemistry contributes to ferroptosis susceptibility is mostly unexplored. Here, we systematically screened structurally diverse fatty acids for their ability to modulate ferroptosis and unexpectedly identified trans-unsaturated fatty acids as potent sensitizers. Compared with its cis counterpart linoleic acid, the trans polyunsaturated fatty acid (PUFA) linoelaidic acid more strongly enhanced lipid peroxidation and promoted the accumulation of ferroptosis-susceptible phospholipid species. Unexpectedly, the trans monounsaturated fatty acid petroselaidic acid also sensitized cells to ferroptosis, whereas its cis stereoisomer petroselinic acid suppressed ferroptosis. Mechanistically, petroselaidic acid required stearoyl-CoA desaturase-dependent conversion to a PUFA, directly demonstrating that double-bond geometry can redirect fatty acid metabolic fate through altered recognition by lipid metabolic enzymes. Although linoelaidic acid and petroselaidic acid followed distinct metabolic pathways, both converged on phospholipid remodeling that expanded pools of ferroptosis-susceptible membrane lipids. Together, our findings demonstrate that fatty acid double-bond geometry determines their metabolic fate and the membrane phospholipid composition, establishing lipid stereochemistry as a previously unrecognized structural determinant of ferroptosis sensitivity.

DOI: https://doi.org/10.64898/2026.07.17.739092

Am J Physiol Cell Physiol. 2026 Jul 29.

Dysregulated Iron Metabolism In Remodeling of Aging Asthmatic Human Airways.

Maunick Lefin Koloko Ngassie, Yamillie Ortiz, Preetham Ravi, Daniel A Pfeffer-Kleemann, Samantha K Hamrick, Michael A Thompson, Yun Hua Fang, Christina M Pabelick, Y S Prakash.

Iron is essential for cellular function, and lung cells are no exception. Previous studies have demonstrated an association between increased level of iron in the lung and aging and age-related lung diseases including pulmonary fibrosis and asthma in the elderly (AIE). However, the mechanisms underlying the accumulation of iron with aging or AIE, or the cell types involved, remain understudied. In the context of asthma, airway smooth muscle is a key cell type contributing to contractility as well as airway remodeling (proliferation, fibrosis). In this study we characterized iron level and regulation in human (hASM) from young (<45 yr), old (≥65 yr) and AIE (≥65 yr) male/female patients, and investigated the contribution of iron overload in hASM to airway remodeling. Cells were treated with ferric ammonium citrate (FAC) (100 μM; 72h) or iron chelator deferoxamine (DFO) (100 µM; 72h). Basal levels of intracellular ferrous iron (Fe2+) were determined using the fluorescent dye FerroOrange. Cell lysates were analyzed for iron accumulation, antioxidant, lipid peroxidation, and extracellular matrix (ECM) markers, and cell proliferation was assessed. We found that iron accumulates with aging, but surprisingly decreases with AIE. hASM from AIE patients showed activated antioxidant pathways and lipid peroxidation, while FAC-exposure impaired iron metabolism and enhanced ECM deposition. Iron depletion mitigated the antioxidant response, lipid peroxidation, cell proliferation, ECM production. These findings suggest that iron metabolism in hASM contributes to cell hyperplasia and ECM, while in aging and particularly AIE, counter-regulatory changes in iron metabolism and antioxidant pathways occur, overall promoting airway remodeling.

Keywords: Airway Smooth Muscle; Antioxidant; Asthma; Ferroptosis; Iron Regulation

DOI: https://doi.org/10.1152/ajpcell.00897.2025