Systemic Regulation of Host Energy and Oogenesis by Microbiome-Derived Mitochondrial Coenzymes

Yulia Gnainsky; Nofar Zfanya; Michael Elgart; Eman Omri; Alexander Brandis; Tevie Mehlman; Maxim Itkin; Sergey Malitsky; Jerzy Adamski; Yoav Soen

doi:10.1016/j.celrep.2020.108583

Systemic Regulation of Host Energy and Oogenesis by Microbiome-Derived Mitochondrial Coenzymes

Yulia Gnainsky, Nofar Zfanya, Michael Elgart, Eman Omri, Alexander Brandis, Tevie Mehlman, Maxim Itkin, Sergey Malitsky, Jerzy Adamski, Yoav Soen

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

Abstract

Gut microbiota have been shown to promote oogenesis and fecundity, but the mechanistic basis of remote influence on oogenesis remained unknown. Here, we report a systemic mechanism of influence mediated by bacterial-derived supply of mitochondrial coenzymes. Removal of microbiota decreased mitochondrial activity and ATP levels in the whole-body and ovary, resulting in repressed oogenesis. Similar repression was caused by RNA-based knockdown of mitochondrial function in ovarian follicle cells. Reduced mitochondrial function in germ-free (GF) females was reversed by bacterial recolonization or supplementation of riboflavin, a precursor of FAD and FMN. Metabolomics analysis of GF females revealed a decrease in oxidative phosphorylation and FAD levels and an increase in metabolites that are degraded by FAD-dependent enzymes (e.g., amino and fatty acids). Riboflavin supplementation opposed this effect, elevating mitochondrial function, ATP, and oogenesis. These findings uncover a bacterial-mitochondrial axis of influence, linking gut bacteria with systemic regulation of host energy and reproduction.

Original language	English
Article number	108583
Number of pages	18
Journal	Cell Reports
Volume	34
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2020.108583
State	Published - 5 Jan 2021

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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title = "Systemic Regulation of Host Energy and Oogenesis by Microbiome-Derived Mitochondrial Coenzymes",

abstract = "Gut microbiota have been shown to promote oogenesis and fecundity, but the mechanistic basis of remote influence on oogenesis remained unknown. Here, we report a systemic mechanism of influence mediated by bacterial-derived supply of mitochondrial coenzymes. Removal of microbiota decreased mitochondrial activity and ATP levels in the whole-body and ovary, resulting in repressed oogenesis. Similar repression was caused by RNA-based knockdown of mitochondrial function in ovarian follicle cells. Reduced mitochondrial function in germ-free (GF) females was reversed by bacterial recolonization or supplementation of riboflavin, a precursor of FAD and FMN. Metabolomics analysis of GF females revealed a decrease in oxidative phosphorylation and FAD levels and an increase in metabolites that are degraded by FAD-dependent enzymes (e.g., amino and fatty acids). Riboflavin supplementation opposed this effect, elevating mitochondrial function, ATP, and oogenesis. These findings uncover a bacterial-mitochondrial axis of influence, linking gut bacteria with systemic regulation of host energy and reproduction.",

author = "Yulia Gnainsky and Nofar Zfanya and Michael Elgart and Eman Omri and Alexander Brandis and Tevie Mehlman and Maxim Itkin and Sergey Malitsky and Jerzy Adamski and Yoav Soen",

note = "We thank Vladimir Kiss and Dr. Reinat Nevo (Weizmann Institute of Science) for intellectual and technical assistance in image analysis. We thank Prof. Michael Walker (Weizmann Institute of Science) and Dr. Yael Heifetz (Hebrew University) for helpful discussions and suggestions, and Maiar Ibrahim and Yael Hanoch for technical and experimental assistance. We also thank the Weizmann Fly{\textquoteright}s core facility for providing technical support and Weizmann Design Brunch for graphical abstract design assistance. This work was supported by the Sir John Templeton Foundation ( 40663 and 61122 ). The work of S.M. and M.I. was supported by the Vera and John Schwartz Family Center for Metabolic Biology . Y.G. and Y.S. designed and supervised the study and wrote the paper. Y.G., N.Z., M.E., and E.O. performed experiments and data analysis. A.B. and T.M. performed targeted measurements of ATP and ADP. S.M. and M.I. performed targeted metabolomics and lipidomics analysis. J.A. performed the initial metabolomics measurements.",

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doi = "10.1016/j.celrep.2020.108583",

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volume = "34",

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T1 - Systemic Regulation of Host Energy and Oogenesis by Microbiome-Derived Mitochondrial Coenzymes

AU - Gnainsky, Yulia

AU - Zfanya, Nofar

AU - Elgart, Michael

AU - Omri, Eman

AU - Brandis, Alexander

AU - Mehlman, Tevie

AU - Itkin, Maxim

AU - Malitsky, Sergey

AU - Adamski, Jerzy

AU - Soen, Yoav

N1 - We thank Vladimir Kiss and Dr. Reinat Nevo (Weizmann Institute of Science) for intellectual and technical assistance in image analysis. We thank Prof. Michael Walker (Weizmann Institute of Science) and Dr. Yael Heifetz (Hebrew University) for helpful discussions and suggestions, and Maiar Ibrahim and Yael Hanoch for technical and experimental assistance. We also thank the Weizmann Fly’s core facility for providing technical support and Weizmann Design Brunch for graphical abstract design assistance. This work was supported by the Sir John Templeton Foundation ( 40663 and 61122 ). The work of S.M. and M.I. was supported by the Vera and John Schwartz Family Center for Metabolic Biology . Y.G. and Y.S. designed and supervised the study and wrote the paper. Y.G., N.Z., M.E., and E.O. performed experiments and data analysis. A.B. and T.M. performed targeted measurements of ATP and ADP. S.M. and M.I. performed targeted metabolomics and lipidomics analysis. J.A. performed the initial metabolomics measurements.

PY - 2021/1/5

Y1 - 2021/1/5

N2 - Gut microbiota have been shown to promote oogenesis and fecundity, but the mechanistic basis of remote influence on oogenesis remained unknown. Here, we report a systemic mechanism of influence mediated by bacterial-derived supply of mitochondrial coenzymes. Removal of microbiota decreased mitochondrial activity and ATP levels in the whole-body and ovary, resulting in repressed oogenesis. Similar repression was caused by RNA-based knockdown of mitochondrial function in ovarian follicle cells. Reduced mitochondrial function in germ-free (GF) females was reversed by bacterial recolonization or supplementation of riboflavin, a precursor of FAD and FMN. Metabolomics analysis of GF females revealed a decrease in oxidative phosphorylation and FAD levels and an increase in metabolites that are degraded by FAD-dependent enzymes (e.g., amino and fatty acids). Riboflavin supplementation opposed this effect, elevating mitochondrial function, ATP, and oogenesis. These findings uncover a bacterial-mitochondrial axis of influence, linking gut bacteria with systemic regulation of host energy and reproduction.

AB - Gut microbiota have been shown to promote oogenesis and fecundity, but the mechanistic basis of remote influence on oogenesis remained unknown. Here, we report a systemic mechanism of influence mediated by bacterial-derived supply of mitochondrial coenzymes. Removal of microbiota decreased mitochondrial activity and ATP levels in the whole-body and ovary, resulting in repressed oogenesis. Similar repression was caused by RNA-based knockdown of mitochondrial function in ovarian follicle cells. Reduced mitochondrial function in germ-free (GF) females was reversed by bacterial recolonization or supplementation of riboflavin, a precursor of FAD and FMN. Metabolomics analysis of GF females revealed a decrease in oxidative phosphorylation and FAD levels and an increase in metabolites that are degraded by FAD-dependent enzymes (e.g., amino and fatty acids). Riboflavin supplementation opposed this effect, elevating mitochondrial function, ATP, and oogenesis. These findings uncover a bacterial-mitochondrial axis of influence, linking gut bacteria with systemic regulation of host energy and reproduction.

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U2 - 10.1016/j.celrep.2020.108583

DO - 10.1016/j.celrep.2020.108583

M3 - مقالة

SN - 2211-1247

VL - 34

JO - Cell Reports

JF - Cell Reports

IS - 1

M1 - 108583

ER -

Systemic Regulation of Host Energy and Oogenesis by Microbiome-Derived Mitochondrial Coenzymes

Abstract

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