Pub Date : 2025-02-07DOI: 10.1016/j.cell.2024.12.032
Young-Jun Park, Chen Liu, Jimin Lee, Jack T. Brown, Cheng-Bao Ma, Peng Liu, Risako Gen, Qing Xiong, Samantha K. Zepeda, Cameron Stewart, Amin Addetia, Caroline J. Craig, M. Alejandra Tortorici, Abeer N. Alshukairi, Tyler N. Starr, Huan Yan, David Veesler
DPP4 was considered a canonical receptor for merbecoviruses until the recent discovery of African bat-borne MERS-related coronaviruses using ACE2. The extent and diversity of ACE2 utilization among merbecoviruses and their receptor species tropism remain unknown. Here, we reveal that HKU5 enters host cells utilizing Pipistrellus abramus (P.abr) and several non-bat mammalian ACE2s through a binding mode distinct from that of any other known ACE2-using coronaviruses. We defined the molecular determinants of receptor species tropism and identified a single amino acid mutation enabling HKU5 to utilize human ACE2, providing proof of principle for machine-learning-assisted outbreak preparedness. We show that MERS-CoV and HKU5 have markedly distinct antigenicity and identified several HKU5 inhibitors, including two clinical compounds. Our findings profoundly alter our understanding of coronavirus evolution, as several merbecovirus clades independently evolved ACE2 utilization, and pave the way for developing countermeasures against viruses poised for human emergence.
{"title":"Molecular basis of convergent evolution of ACE2 receptor utilization among HKU5 coronaviruses","authors":"Young-Jun Park, Chen Liu, Jimin Lee, Jack T. Brown, Cheng-Bao Ma, Peng Liu, Risako Gen, Qing Xiong, Samantha K. Zepeda, Cameron Stewart, Amin Addetia, Caroline J. Craig, M. Alejandra Tortorici, Abeer N. Alshukairi, Tyler N. Starr, Huan Yan, David Veesler","doi":"10.1016/j.cell.2024.12.032","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.032","url":null,"abstract":"DPP4 was considered a canonical receptor for merbecoviruses until the recent discovery of African bat-borne MERS-related coronaviruses using ACE2. The extent and diversity of ACE2 utilization among merbecoviruses and their receptor species tropism remain unknown. Here, we reveal that HKU5 enters host cells utilizing <em>Pipistrellus abramus</em> (<em>P.abr</em>) and several non-bat mammalian ACE2s through a binding mode distinct from that of any other known ACE2-using coronaviruses. We defined the molecular determinants of receptor species tropism and identified a single amino acid mutation enabling HKU5 to utilize human ACE2, providing proof of principle for machine-learning-assisted outbreak preparedness. We show that MERS-CoV and HKU5 have markedly distinct antigenicity and identified several HKU5 inhibitors, including two clinical compounds. Our findings profoundly alter our understanding of coronavirus evolution, as several merbecovirus clades independently evolved ACE2 utilization, and pave the way for developing countermeasures against viruses poised for human emergence.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"79 2 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.cell.2024.12.003
Gianluca Mauri, Giorgio Patelli, Giovanni Crisafulli, Salvatore Siena, Alberto Bardelli
The incidence of early-onset colorectal cancer (EO-CRC) is surging, and by 2030, one-third of all CRCs will occur before the commonly recommended screening age of 50 years. The time required for EO-CRC to reach the metastatic stage is unknown, yet this knowledge is critical to tailor early-diagnosis screening strategies. Here, we discuss how defining a key biological feature of EO-CRC may be central to protecting young adults from an alarming and probably unprecedented tumor epidemic.
{"title":"Tumor “age” in early-onset colorectal cancer","authors":"Gianluca Mauri, Giorgio Patelli, Giovanni Crisafulli, Salvatore Siena, Alberto Bardelli","doi":"10.1016/j.cell.2024.12.003","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.003","url":null,"abstract":"The incidence of early-onset colorectal cancer (EO-CRC) is surging, and by 2030, one-third of all CRCs will occur before the commonly recommended screening age of 50 years. The time required for EO-CRC to reach the metastatic stage is unknown, yet this knowledge is critical to tailor early-diagnosis screening strategies. Here, we discuss how defining a key biological feature of EO-CRC may be central to protecting young adults from an alarming and probably unprecedented tumor epidemic.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.cell.2025.01.024
Jaime L. Schneider, Kiran Kurmi, Yutong Dai, Ishita Dhiman, Shakchhi Joshi, Brandon M. Gassaway, Christian W. Johnson, Nicole Jones, Zongyu Li, Christian P. Joschko, Toshio Fujino, Joao A. Paulo, Satoshi Yoda, Gerard Baquer, Daniela Ruiz, Sylwia A. Stopka, Liam Kelley, Andrew Do, Mari Mino-Kenudson, Lecia V. Sequist, Marcia C. Haigis
Little is known about metabolic vulnerabilities in oncogene-driven lung cancer. Here, we perform a phosphoproteomic screen in anaplastic lymphoma kinase (ALK)-rearranged (“ALK+”) patient-derived cell lines and identify guanylate kinase 1 (GUK1), a guanosine diphosphate (GDP)-synthesizing enzyme, as a target of ALK signaling in lung cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis. Spatial imaging of ALK+ patient tumor specimens shows enhanced phosphorylation of GUK1 that significantly correlates with guanine nucleotides in situ. Abrogation of GUK1 phosphorylation reduces intracellular GDP and guanosine triphosphate (GTP) pools and decreases mitogen-activated protein kinase (MAPK) signaling and Ras-GTP loading. A GUK1 variant that cannot be phosphorylated (Y74F) decreases tumor proliferation in vitro and in vivo. Beyond ALK, other oncogenic fusion proteins in lung cancer also regulate GUK1 phosphorylation. These studies may pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.
{"title":"GUK1 activation is a metabolic liability in lung cancer","authors":"Jaime L. Schneider, Kiran Kurmi, Yutong Dai, Ishita Dhiman, Shakchhi Joshi, Brandon M. Gassaway, Christian W. Johnson, Nicole Jones, Zongyu Li, Christian P. Joschko, Toshio Fujino, Joao A. Paulo, Satoshi Yoda, Gerard Baquer, Daniela Ruiz, Sylwia A. Stopka, Liam Kelley, Andrew Do, Mari Mino-Kenudson, Lecia V. Sequist, Marcia C. Haigis","doi":"10.1016/j.cell.2025.01.024","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.024","url":null,"abstract":"Little is known about metabolic vulnerabilities in oncogene-driven lung cancer. Here, we perform a phosphoproteomic screen in anaplastic lymphoma kinase (<em>ALK</em>)-rearranged (“ALK+”) patient-derived cell lines and identify guanylate kinase 1 (GUK1), a guanosine diphosphate (GDP)-synthesizing enzyme, as a target of ALK signaling in lung cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis. Spatial imaging of ALK+ patient tumor specimens shows enhanced phosphorylation of GUK1 that significantly correlates with guanine nucleotides <em>in situ</em>. Abrogation of GUK1 phosphorylation reduces intracellular GDP and guanosine triphosphate (GTP) pools and decreases mitogen-activated protein kinase (MAPK) signaling and Ras-GTP loading. A GUK1 variant that cannot be phosphorylated (Y74F) decreases tumor proliferation <em>in vitro</em> and <em>in vivo</em>. Beyond ALK, other oncogenic fusion proteins in lung cancer also regulate GUK1 phosphorylation. These studies may pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"62 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.cell.2025.01.014
Nyasha Milanzi
Nyasha Milanzi is a winner of the fifth annual Rising Black Scientists Awards for a scholar in the physical, data, earth, and environmental sciences. We asked emerging Black scientists to tell us about their scientific vision and goals, experiences that sparked their interest in science, how they want to contribute to a more inclusive scientific community, and how these all fit together on their journey. This is her story.
{"title":"Inspiring the next generation of engineers and scientists to be champions of equitable change","authors":"Nyasha Milanzi","doi":"10.1016/j.cell.2025.01.014","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.014","url":null,"abstract":"Nyasha Milanzi is a winner of the fifth annual Rising Black Scientists Awards for a scholar in the physical, data, earth, and environmental sciences. We asked emerging Black scientists to tell us about their scientific vision and goals, experiences that sparked their interest in science, how they want to contribute to a more inclusive scientific community, and how these all fit together on their journey. This is her story.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"5 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.cell.2025.01.010
Victor Ekuta
Victor Ekuta is a winner of the fifth annual Rising Black Scientists Awards for a scholar in the life and health sciences. We asked emerging Black scientists to tell us about their scientific vision and goals, the experiences that sparked their interest in science, how they want to contribute to a more inclusive scientific community, and how these all fit together on their journey. This is his story.
{"title":"Retooling science: Transforming tools into instruments of equity as a Black physician-scientist","authors":"Victor Ekuta","doi":"10.1016/j.cell.2025.01.010","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.010","url":null,"abstract":"Victor Ekuta is a winner of the fifth annual Rising Black Scientists Awards for a scholar in the life and health sciences. We asked emerging Black scientists to tell us about their scientific vision and goals, the experiences that sparked their interest in science, how they want to contribute to a more inclusive scientific community, and how these all fit together on their journey. This is his story.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"11 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.cell.2025.01.009
Jheannelle Johnson
Jheannelle Johnson is a winner of the fifth annual Rising Black Scientists Awards for a scholar in the life and health sciences. We asked emerging Black scientists to tell us about their scientific vision and goals, experiences that sparked their interest in science, how they want to contribute to a more inclusive scientific community, and how these all fit together on their journey. This is her story.
{"title":"The sounds of music: Tracing memories and pathways through research and resistance","authors":"Jheannelle Johnson","doi":"10.1016/j.cell.2025.01.009","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.009","url":null,"abstract":"Jheannelle Johnson is a winner of the fifth annual Rising Black Scientists Awards for a scholar in the life and health sciences. We asked emerging Black scientists to tell us about their scientific vision and goals, experiences that sparked their interest in science, how they want to contribute to a more inclusive scientific community, and how these all fit together on their journey. This is her story.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"11 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.cell.2025.01.013
Kenna Gloria Agbugba
Kenna Gloria Agbugba is a winner of the fifth annual Rising Black Scientists Awards for a scholar in the physical, data, earth, and environmental sciences. We asked emerging Black scientists to tell us about their scientific vision and goals, the experiences that sparked their interest in science, how they want to contribute to a more inclusive scientific community, and how these all fit together on their journey. This is her story.
Kenna Gloria Agbugba 是第五届 "黑人科学家崛起奖"（Rising Black Scientists Awards）物理、数据、地球和环境科学领域的获奖者。我们请新崛起的黑人科学家告诉我们他们的科学愿景和目标、激发他们对科学的兴趣的经历、他们希望如何为一个更具包容性的科学界做出贡献，以及这些在他们的人生旅途中是如何结合在一起的。这就是她的故事。
{"title":"Bridging worlds: A STEM journey from Nigeria to the US and back","authors":"Kenna Gloria Agbugba","doi":"10.1016/j.cell.2025.01.013","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.013","url":null,"abstract":"Kenna Gloria Agbugba is a winner of the fifth annual Rising Black Scientists Awards for a scholar in the physical, data, earth, and environmental sciences. We asked emerging Black scientists to tell us about their scientific vision and goals, the experiences that sparked their interest in science, how they want to contribute to a more inclusive scientific community, and how these all fit together on their journey. This is her story.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"137 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-05DOI: 10.1016/j.cell.2025.01.018
Srikanta Chowdhury, Nachiket G. Kamatkar, Wendy Xueyi Wang, Christa A. Akerele, Jiahao Huang, Junlin Wu, Amajindi Nwankpa, Charlotte M. Kane, Varun M. Bhave, Hao Huang, Xiao Wang, Alexander R. Nectow
Hunger is evolutionarily hardwired to ensure that an animal has sufficient energy to survive and reproduce. Just as important as knowing when to start eating is knowing when to stop eating. Here, using spatially resolved single-cell phenotyping, we characterize a population of neuropeptidergic neurons in the brainstem’s dorsal raphe nucleus (DRN) and describe how they regulate satiation. These neurons track food from sensory presentation through ingestion, integrate these signals with slower-acting humoral cues, and express cholecystokinin (CCK). These CCK neurons bidirectionally regulate meal size, driving a sustained meal termination signal with a built-in delay. They are also well positioned to sense and respond to ingestion: they express a host of metabolic signaling factors and are integrated into an extended network known to regulate feeding. Together, this work demonstrates how DRN CCK neurons regulate satiation and identifies a likely conserved cellular mechanism that transforms diverse neurohumoral signals into a key behavioral output.
{"title":"Brainstem neuropeptidergic neurons link a neurohumoral axis to satiation","authors":"Srikanta Chowdhury, Nachiket G. Kamatkar, Wendy Xueyi Wang, Christa A. Akerele, Jiahao Huang, Junlin Wu, Amajindi Nwankpa, Charlotte M. Kane, Varun M. Bhave, Hao Huang, Xiao Wang, Alexander R. Nectow","doi":"10.1016/j.cell.2025.01.018","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.018","url":null,"abstract":"Hunger is evolutionarily hardwired to ensure that an animal has sufficient energy to survive and reproduce. Just as important as knowing when to start eating is knowing when to stop eating. Here, using spatially resolved single-cell phenotyping, we characterize a population of neuropeptidergic neurons in the brainstem’s dorsal raphe nucleus (DRN) and describe how they regulate satiation. These neurons track food from sensory presentation through ingestion, integrate these signals with slower-acting humoral cues, and express cholecystokinin (CCK). These CCK neurons bidirectionally regulate meal size, driving a sustained meal termination signal with a built-in delay. They are also well positioned to sense and respond to ingestion: they express a host of metabolic signaling factors and are integrated into an extended network known to regulate feeding. Together, this work demonstrates how DRN CCK neurons regulate satiation and identifies a likely conserved cellular mechanism that transforms diverse neurohumoral signals into a key behavioral output.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"11 227 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-05DOI: 10.1016/j.cell.2025.01.017
Haosheng Shen, Nikhil Aggarwal, Beiming Cui, Guo Wei Foo, Yuanzhi He, Santosh Kumar Srivastava, Shengjie Li, Marcus Ze Xian Seah, Kwok Soon Wun, Hua Ling, In Young Hwang, Chun Loong Ho, Yung Seng Lee, Matthew Wook Chang
Intranasal administration through the olfactory epithelium (OE) presents a direct pathway for brain-targeted therapeutic delivery, although its feasibility is hampered by the anatomical and absorptive limitations of the OE. In this study, we identified Lactobacillus plantarum WCFS1 (Lp), a commensal strain with a natural affinity for the OE and engineered it to function as a vector for cerebral drug delivery. Upon intranasal administration, Lp released specific payload molecules within the OE, with subsequent transport and accumulation in the brain. The therapeutic efficacy of Lp was further validated by the recombinant production and secretion of appetite-regulating hormones. When administered intranasally in a murine model of obesity prevention, the engineered Lp significantly alleviated obesity-related symptoms. This was evidenced by decreased appetite, reduced body weight gain, and improved glucose metabolism and fat mass deposition. Our study demonstrates the capability of Lp as an intranasal delivery vehicle, emphasizing its potential for brain-targeted therapeutic applications.
{"title":"Engineered commensals for targeted nose-to-brain drug delivery","authors":"Haosheng Shen, Nikhil Aggarwal, Beiming Cui, Guo Wei Foo, Yuanzhi He, Santosh Kumar Srivastava, Shengjie Li, Marcus Ze Xian Seah, Kwok Soon Wun, Hua Ling, In Young Hwang, Chun Loong Ho, Yung Seng Lee, Matthew Wook Chang","doi":"10.1016/j.cell.2025.01.017","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.017","url":null,"abstract":"Intranasal administration through the olfactory epithelium (OE) presents a direct pathway for brain-targeted therapeutic delivery, although its feasibility is hampered by the anatomical and absorptive limitations of the OE. In this study, we identified <em>Lactobacillus plantarum</em> WCFS1 (Lp), a commensal strain with a natural affinity for the OE and engineered it to function as a vector for cerebral drug delivery. Upon intranasal administration, Lp released specific payload molecules within the OE, with subsequent transport and accumulation in the brain. The therapeutic efficacy of Lp was further validated by the recombinant production and secretion of appetite-regulating hormones. When administered intranasally in a murine model of obesity prevention, the engineered Lp significantly alleviated obesity-related symptoms. This was evidenced by decreased appetite, reduced body weight gain, and improved glucose metabolism and fat mass deposition. Our study demonstrates the capability of Lp as an intranasal delivery vehicle, emphasizing its potential for brain-targeted therapeutic applications.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"55 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-04DOI: 10.1016/j.cell.2024.12.007
Jonathan Valeros, Madison Jerome, Tenzin Tseyang, Paula Vo, Thang Do, Diana Fajardo Palomino, Nils Grotehans, Manisha Kunala, Alexandra E. Jerrett, Nicolai R. Hathiramani, Michael Mireku, Rayna Y. Magesh, Batuhan Yenilmez, Paul C. Rosen, Jessica L. Mann, Jacob W. Myers, Tenzin Kunchok, Tanner L. Manning, Lily N. Boercker, Paige E. Carr, Jessica B. Spinelli
Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O2 levels. The RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O2 to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure in vitro and in vivo. Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.
{"title":"Rhodoquinone carries electrons in the mammalian electron transport chain","authors":"Jonathan Valeros, Madison Jerome, Tenzin Tseyang, Paula Vo, Thang Do, Diana Fajardo Palomino, Nils Grotehans, Manisha Kunala, Alexandra E. Jerrett, Nicolai R. Hathiramani, Michael Mireku, Rayna Y. Magesh, Batuhan Yenilmez, Paul C. Rosen, Jessica L. Mann, Jacob W. Myers, Tenzin Kunchok, Tanner L. Manning, Lily N. Boercker, Paige E. Carr, Jessica B. Spinelli","doi":"10.1016/j.cell.2024.12.007","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.007","url":null,"abstract":"Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O<sub>2</sub>). In hypoxia, ubiquinol (UQH<sub>2</sub>) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O<sub>2</sub> levels. The RQ/fumarate ETC is strictly present <em>in vivo</em> and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O<sub>2</sub> to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure <em>in vitro</em> and <em>in vivo</em>. Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"25 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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