puc-header

A Hydride Transfer Complex Reprograms NAD Metabolism Preventing Senescence

85 Pages Posted: 22 Dec 2020 Publication Status: Review Complete

See all articles by Sebastian Igelmann

Sebastian Igelmann

Université de Montréal - Department of Biochemistry and Molecular Medicine

Frédéric Lessard

Université de Montréal - Department of Biochemistry and Molecular Medicine

Ana Fernandez-Ruiz

CRCHUM

Jacob Bouchard

Université de Montréal - Department of Biochemistry and Molecular Medicine

Oro Uchenunu

Jewish General Hospital - Lady Davis Institute for Medical Research

Marie-Camille Rowell

CRCHUM

Stéphane Lopes-Paciência

CRCHUM

David Papadopoli

Jewish General Hospital - Lady Davis Institute for Medical Research

Aurélien Fouillen

Université de Montréal - Department of Biochemistry and Molecular Medicine

Katja Julissa Ponce

Université de Montréal - Department of Biochemistry and Molecular Medicine

Geneviève Huot

Université de Montréal - Department of Biochemistry and Molecular Medicine

Lian Mignacca

Université de Montréal - Department of Biochemistry and Molecular Medicine

Mehdi Benfdil

Université de Montréal - Department of Biochemistry and Molecular Medicine

Paloma Kalegari

Université de Montréal - Department of Biochemistry and Molecular Medicine

Haytham M Wahba

Université de Montréal - Department of Biochemistry and Molecular Medicine

Jan Pencik

Medical University of Vienna - Department of Pathology

Nhung Vuong

CRCHUM

Jordan Quenneville

Université de Montréal - Institut de Recherche en Immunologie et en Cancérologie (IRIC)

Véronique Bourdeau

Université de Montréal - Department of Biochemistry and Molecular Medicine

Laura Hulea

Université de Montréal - Département de Médecine

Etienne Gagnon

Université de Montréal - Institut de Recherche en Immunologie et en Cancérologie (IRIC)

Lukas Kenner

Medical University of Vienna - Department of Pathology

Richard Moriggl

University of Veterinary Medicine Vienna - Institute of Animal Breeding and Genetics

Antonio Nanci

Université de Montréal - Department of Biochemistry and Molecular Medicine

Michael Pollak

Jewish General Hospital - Lady Davis Institute for Medical Research

James Omichinski

Université de Montréal - Department of Biochemistry and Molecular Medicine

Ivan Topisitrovic

Jewish General Hospital - Lady Davis Institute for Medical Research

Gerardo Ferbeyre

Université de Montréal - Department of Biochemistry and Molecular Medicine

More...

Abstract

Metabolic rewiring and redox balance play pivotal roles in cancer. Cellular senescence is a barrier for tumorigenesis circumvented in cancer cells by poorly understood mechanisms. We report a novel multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP +. This hydride transfer complex (HTC) is assembled by Malate Dehydrogenase-1, Malic Enzyme-1 and cytosolic Pyruvate Carboxylase. HTC enzymes are found in phase-separated bodies in the cytosol of cancer cells and can be assembled in vitro from purified proteins. They are repressed in senescent cells but induced by p53 inactivation. HTC enzymes are highly expressed in mouse and human prostate cancer models and their inactivation triggers senescence. Exogenous expression of HTC is sufficient to bypass senescence, rescue cells from complex I inhibitors and cooperate with oncogenic RAS to transform primary cells. We provide evidence for a new multi-enzymatic complex that reprograms metabolism and prevents cellular senescence.

Keywords: NAD, NADPH, cellular senescence, mitochondrial dysfunction, MDH1, ME1, PC, metabolon

Suggested Citation

Igelmann, Sebastian and Lessard, Frédéric and Fernandez-Ruiz, Ana and Bouchard, Jacob and Uchenunu, Oro and Rowell, Marie-Camille and Lopes-Paciência, Stéphane and Papadopoli, David and Fouillen, Aurélien and Ponce, Katja Julissa and Huot, Geneviève and Mignacca, Lian and Benfdil, Mehdi and Kalegari, Paloma and Wahba, Haytham M and Pencik, Jan and Vuong, Nhung and Quenneville, Jordan and Bourdeau, Véronique and Hulea, Laura and Gagnon, Etienne and Kenner, Lukas and Moriggl, Richard and Nanci, Antonio and Pollak, Michael and Omichinski, James and Topisitrovic, Ivan and Ferbeyre, Gerardo, A Hydride Transfer Complex Reprograms NAD Metabolism Preventing Senescence. Available at SSRN: https://ssrn.com/abstract=3753808 or http://dx.doi.org/10.2139/ssrn.3753808
This version of the paper has not been formally peer reviewed.

Sebastian Igelmann

Université de Montréal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Frédéric Lessard

Université de Montréal - Department of Biochemistry and Molecular Medicine

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Jacob Bouchard

Université de Montréal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Oro Uchenunu

Jewish General Hospital - Lady Davis Institute for Medical Research

5750 Côte-des-Neiges Rd
Montreal, QC H3S 1Y9
Canada

David Papadopoli

Jewish General Hospital - Lady Davis Institute for Medical Research ( email )

5750 Côte-des-Neiges Rd
Montreal, QC H3S 1Y9
Canada

Aurélien Fouillen

Université de Montréal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Katja Julissa Ponce

Université de Montréal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Geneviève Huot

Université de Montréal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Lian Mignacca

Université de Montréal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Mehdi Benfdil

Université de Montréal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Paloma Kalegari

Université de Montréal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Haytham M Wahba

Université de Montréal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Jan Pencik

Medical University of Vienna - Department of Pathology ( email )

Vienna
Austria

Nhung Vuong

CRCHUM ( email )

Jordan Quenneville

Université de Montréal - Institut de Recherche en Immunologie et en Cancérologie (IRIC) ( email )

2900 Édouard-Montpetit Blvd.
Montreal, Quebec H3T 1J4
Canada

Véronique Bourdeau

Université de Montréal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Laura Hulea

Université de Montréal - Département de Médecine ( email )

2900 Édouard-Montpetit Blvd.
Montreal, Quebec H3T 1J4
Canada

Etienne Gagnon

Université de Montréal - Institut de Recherche en Immunologie et en Cancérologie (IRIC)

2900 Édouard-Montpetit Blvd.
Montreal, Quebec H3T 1J4
Canada

Lukas Kenner

Medical University of Vienna - Department of Pathology ( email )

Vienna
Austria

Richard Moriggl

University of Veterinary Medicine Vienna - Institute of Animal Breeding and Genetics ( email )

Veterinärpl. 1
1210 Wien
Austria

Antonio Nanci

Université de Montréal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Michael Pollak

Jewish General Hospital - Lady Davis Institute for Medical Research ( email )

5750 Côte-des-Neiges Rd
Montreal, QC H3S 1Y9
Canada

James Omichinski

Université de Montréal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Ivan Topisitrovic

Jewish General Hospital - Lady Davis Institute for Medical Research ( email )

5750 Côte-des-Neiges Rd
Montreal, QC H3S 1Y9
Canada

Gerardo Ferbeyre (Contact Author)

Université de Montréal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Click here to go to Cell.com

Paper statistics

Abstract Views
218
Downloads
25
PlumX Metrics