Citations 2
Approaches to reduce succinate accumulation by restoration of succinate dehydrogenase activity in cultured adrenal cells
Khazal, Fatimah Al, Rahimi, Leili , Feng, Fan , Becker, Nicole A. , Maher, L. James , Al Khazal, Fatimah, Folmes, Clifford D, III, Louis James Maher , Feng, Fan, Folmes, Clifford D.L. , Favier, Judith
Journal of Cell Science | April 16, 2025 | Volume: 138 | Issue: 9 | Pages: No page available
ABSTRACT The rare human neuroendocrine tumors pheochromocytoma and paraganglioma (PPGL) can result from loss of mitochondrial succinate dehydrogenase. The resulting succinate accumulation is tumorigenic in certain neuroendocrine cells. Here, we explore two theoretical approaches to mitigate tumorigenic succinate accumulation in a cell culture model of PPGL. We first study a gene replacement strategy using transposition technology, and conclude that many of the changes in mitochondrial morphology, oxidative cell metabolism and succinate accumulation can be reversed by this process. We then investigate whether riboflavin supplementation has the potential to rescue succinate dehydrogenase activity in the intact SDHA catalytic subunit to suppress succinate accumulation even in the absence of SDHB. We show that this latter strategy is not successful.
Convergent Genetic Adaptation in Human Tumors Developed Under Systemic Hypoxia and in Populations Living at High Altitudes
Arenillas, Carlota , Celada, Lucía , Ruiz-Cantador, José , Calsina, Bruna , Datta, Debayan , García‐Galea, Eduardo , Fasani, Roberta , Moreno-Cárdenas, Ana Belén , Alba‐Linares, Juan José , Miranda, Berta , Martínez‐Montes, Ángel M. , Álvarez-Escolá, Cristina , Lecumberri, Beatriz , García, Ana González , Flores, Shahida K., Esquivel, Emmanuel , Ding, Yanli , Peitzsch, Mirko , Robles-Guirado, José-Ángel , Zapata, Rita Maria Regojo , Iglesias, Carmela , Dwight, Trisha , Oleaga, Amelia , Garrido‐Lestache, Elvira , Marín, María Jesús del Cerro , Martínez-Bendayán, Isaac , Álvarez-González, Enol , Cubiella, Tamara, Lourenço, Delmar Muniz , Pereira, Maria Adelaide Albergaria, Burnichon, Nelly , Broberg, Craig S. , Dickson, Paxton V. , Soriano, Joaquín Rueda , Dienstmann, Rodrigo , Villanueva, Josep , Capdevila, Jaume , Gimenez‐Roqueplo, Anne‐Paule , Bechmann, Nicole , Vaidya, Anand , Weghorn, Donate , Casteràs, Anna , Adameyko, Igor , Miranda-Barrio, Berta , González García, Ana , K Flores, Shahida , Regojo Zapata, Rita Maria , Pozo-Kreilinger, José Juan , Iglesias, Carmela , Dwight, Trisha , Muir, Christopher A , Oleaga, Amelia , Garrido-Lestache Rodríguez-Monte, Maria Elvira , Del Cerro, Maria Jesús , Martínez-Bendayán, Isaac , Álvarez-González, Enol , Cubiella, Tamara , Lourenço, Delmar Muniz , A Pereira, Maria Adelaide , Burnichon, Nelly , Buffet, Alexandre , Broberg, Craig , Dickson, Paxton V , Fraga, Mario F , Llorente Pendás, José Luis , Rueda Soriano, Joaquín , Buendía Fuentes, Francisco , Toledo, Sergio P A , Clifton-Bligh, Roderick , Dienstmann, Rodrigo , Villanueva, Josep , Capdevila, Jaume , Gimenez-Roqueplo, Anne-Paule , Favier, Judith , Nuciforo, Paolo , Young, W F , Bechmann, Nicole , Opotowsky, Alexander R , Vaidya, Anand , Bancos, Irina , Weghorn, Donate , Robledo, Mercedes , Casteràs, Anna , Dos-Subirà, Laura , Adameyko, Igor , Chiara, María-Dolores , Dahia, Patricia L M , Toledo, Rodrigo A , Fraga, Mario F. , Nucíforo, Paolo , Young, William F. , Bancos, Irina , Chiara, María‐Dolores , Dahia, Patricia L. M.
Cancer Discovery | April 8, 2025 | Volume: 15 | Issue: 5 | Pages: 1037-1062
Abstract This study explores parallels between systemic hypoxia adaptation in high-altitude populations and tumorigenesis. We identified EPAS1, a gene critical for hypoxia adaptation in populations such as Tibetans and Sherpas, as playing a similar adaptive role in tumors arising under hypoxic conditions. Tumors from patients with chronic hypoxia displayed impaired DNA repair and frequent emergence of EPAS1 variants, with frequencies reaching up to 90%, echoing the positive selection seen in high-altitude dwellers. Mechanistically, EPAS1 gain-of-function mutations promote COX4I2 expression, reducing cellular oxygen consumption and supporting tumor proliferation in hypoxia. Analysis of clinical data from patients with hypoxia revealed tissue-specific and time-sensitive tumorigenic effects, particularly impacting oxygen-sensitive cells in the postnatal period. Our findings suggest that EPAS1-driven adaptation mechanisms in high-altitude populations provide a model for understanding tumor evolution under hypoxic stress, highlighting how genetic adaptations to diverse stressors in natural populations may yield insights into tumorigenesis and cancer progression. Significance: This study reveals a broad convergence in genetic adaptation to hypoxia between natural populations and tumors, suggesting that insights from natural populations could enhance our understanding of cancer biology and identify novel therapeutic targets. See related commentary by Lee, p. 875