Metabolic determinants of cellular fitness dependent on mitochondrial reactive oxygen species

Mitochondria-derived reactive oxygen species (mROS) are required for the survival, proliferation, and metastasis of cancer cells. The mechanism by which mitochondrial metabolism regulates mROS levels to support cancer cells is not fully understood. To address this, we conducted a metabolism-focused CRISPR-Cas9 genetic screen and uncovered that loss of genes encoding subunits of mitochondrial complex I was deleterious in the presence of the mitochondria-targeted antioxidant mito-vitamin E (MVE). Genetic or pharmacologic inhibition of mitochondrial complex I in combination with the mitochondria-targeted antioxidants, MVE or MitoTEMPO, induced a robust integrated stress response (ISR) and markedly diminished cell survival and proliferation in vitro. This was not observed following inhibition of mitochondrial complex III. Administration of MitoTEMPO in combination with the mitochondrial complex I inhibitor phenformin decreased the leukemic burden in a mouse model of T cell acute lymphoblastic leukemia. Thus, mitochondrial complex I is a dominant metabolic determinant of mROS-dependent cellular fitness.

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Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species

Cell Death and Disease ◽

10.1038/cddis.2013.204 ◽

2013 ◽

Vol 4 (6) ◽

pp. e681-e681 ◽

Cited By ~ 48

Author(s):

C-W Cheng ◽

C-Y Kuo ◽

C-C Fan ◽

W-C Fang ◽

S S Jiang ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Cancer Cells ◽

Complex I ◽

Reactive Oxygen ◽

Mitochondrial Complex I ◽

Oxygen Species ◽

Mitochondrial Complex ◽

Aggressive Phenotype

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Do semiquinones formed by mitochondrial complex I contribute to reactive oxygen species production?

Biochimica et Biophysica Acta (BBA) - Bioenergetics ◽

10.1016/j.bbabio.2010.04.201 ◽

2010 ◽

Vol 1797 ◽

pp. 61-62

Author(s):

Kenneth R. Pryde ◽

Judy Hirst

Keyword(s):

Reactive Oxygen Species ◽

Complex I ◽

Reactive Oxygen Species Production ◽

Reactive Oxygen ◽

Mitochondrial Complex I ◽

Oxygen Species ◽

Mitochondrial Complex ◽

Species Production

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The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species

Developmental Cell ◽

10.1016/j.devcel.2017.02.020 ◽

2017 ◽

Vol 40 (6) ◽

pp. 583-594.e6 ◽

Cited By ~ 172

Author(s):

Evan A. Bordt ◽

Pascaline Clerc ◽

Brian A. Roelofs ◽

Andrew J. Saladino ◽

László Tretter ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Complex I ◽

Reactive Oxygen ◽

Mitochondrial Complex I ◽

Oxygen Species ◽

Mitochondrial Complex ◽

Mitochondrial Complex I Inhibitor

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Nitrite Therapy After Cardiac Arrest Reduces Reactive Oxygen Species Generation, Improves Cardiac and Neurological Function, and Enhances Survival via Reversible Inhibition of Mitochondrial Complex I

Yearbook of Anesthesiology and Pain Management ◽

10.1016/j.yane.2010.12.001 ◽

2011 ◽

Vol 2011 ◽

pp. 220-222

Author(s):

M. Mathru

Keyword(s):

Reactive Oxygen Species ◽

Cardiac Arrest ◽

Complex I ◽

Reactive Oxygen Species Generation ◽

Reactive Oxygen ◽

Neurological Function ◽

Mitochondrial Complex I ◽

Oxygen Species ◽

Mitochondrial Complex ◽

Reversible Inhibition

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Fluazinam targets mitochondrial complex I to induce reactive oxygen species-dependent cytotoxicity in SH-SY5Y cells

Neurochemistry International ◽

10.1016/j.neuint.2012.03.007 ◽

2012 ◽

Vol 60 (8) ◽

pp. 773-781 ◽

Cited By ~ 12

Author(s):

Jeong Eun Lee ◽

Jin Sun Kang ◽

Yeo-Woon Ki ◽

Jae Hyeon Park ◽

In Chul Shin ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Complex I ◽

Reactive Oxygen ◽

Mitochondrial Complex I ◽

Oxygen Species ◽

Mitochondrial Complex

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The Neuronal Mitochondrial Complex I Reactive Oxygen Species Nanodomain Mediates Hypoxic Avoidance Responses in C. elegans

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2020.10.189 ◽

2020 ◽

Vol 159 ◽

pp. S72

Author(s):

John Onukwufor ◽

M. Farooqi ◽

Andrew Wojtovich

Keyword(s):

Reactive Oxygen Species ◽

Complex I ◽

Reactive Oxygen ◽

Mitochondrial Complex I ◽

Oxygen Species ◽

Mitochondrial Complex ◽

C Elegans ◽

Avoidance Responses

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Diphenyleneiodonium acutely inhibits reactive oxygen species production by mitochondrial complex I during reverse, but not forward electron transport

Biochimica et Biophysica Acta (BBA) - Bioenergetics ◽

10.1016/j.bbabio.2008.03.005 ◽

2008 ◽

Vol 1777 (5) ◽

pp. 397-403 ◽

Cited By ~ 74

Author(s):

Adrian J. Lambert ◽

Julie A. Buckingham ◽

Helen M. Boysen ◽

Martin D. Brand

Keyword(s):

Reactive Oxygen Species ◽

Electron Transport ◽

Complex I ◽

Reactive Oxygen Species Production ◽

Reactive Oxygen ◽

Mitochondrial Complex I ◽

Oxygen Species ◽

Mitochondrial Complex ◽

Species Production

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The Selective Toxicity of 1-Methyl-4-phenylpyridinium to Dopaminergic Neurons: The Role of Mitochondrial Complex I and Reactive Oxygen Species Revisited

Molecular Pharmacology ◽

10.1124/mol.58.2.271 ◽

2000 ◽

Vol 58 (2) ◽

pp. 271-278 ◽

Cited By ~ 68

Author(s):

Ken Nakamura ◽

Vytautas P. Bindokas ◽

Jeremy D. Marks ◽

David A. Wright ◽

David M. Frim ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Dopaminergic Neurons ◽

Complex I ◽

Reactive Oxygen ◽

Mitochondrial Complex I ◽

Oxygen Species ◽

Mitochondrial Complex ◽

Selective Toxicity

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Caenorhabditis elegans chronically exposed to a Mn/Zn ethylene-bis-dithiocarbamate fungicide show mitochondrial Complex I inhibition and increased reactive oxygen species

NeuroToxicology ◽

10.1016/j.neuro.2016.07.011 ◽

2016 ◽

Vol 56 ◽

pp. 170-179 ◽

Cited By ~ 11

Author(s):

Denise C. Bailey ◽

Callie E. Todt ◽

Sarah E. Orfield ◽

Rachel D. Denney ◽

Isaac B. Snapp ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Caenorhabditis Elegans ◽

Complex I ◽

Reactive Oxygen ◽

Mitochondrial Complex I ◽

Oxygen Species ◽

Mitochondrial Complex

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Physiologic Implications of Reactive Oxygen Species Production by Mitochondrial Complex I Reverse Electron Transport

Antioxidants ◽

10.3390/antiox8080285 ◽

2019 ◽

Vol 8 (8) ◽

pp. 285 ◽

Cited By ~ 11

Author(s):

John O. Onukwufor ◽

Brandon J. Berry ◽

Andrew P. Wojtovich

Keyword(s):

Reactive Oxygen Species ◽

Electron Transport ◽

Complex I ◽

Reactive Oxygen ◽

Reverse Direction ◽

Mitochondrial Complex I ◽

Ros Production ◽

Oxygen Species ◽

Mitochondrial Complex ◽

Reverse Electron Transport

Mitochondrial reactive oxygen species (ROS) can be either detrimental or beneficial depending on the amount, duration, and location of their production. Mitochondrial complex I is a component of the electron transport chain and transfers electrons from NADH to ubiquinone. Complex I is also a source of ROS production. Under certain thermodynamic conditions, electron transfer can reverse direction and reduce oxygen at complex I to generate ROS. Conditions that favor this reverse electron transport (RET) include highly reduced ubiquinone pools, high mitochondrial membrane potential, and accumulated metabolic substrates. Historically, complex I RET was associated with pathological conditions, causing oxidative stress. However, recent evidence suggests that ROS generation by complex I RET contributes to signaling events in cells and organisms. Collectively, these studies demonstrate that the impact of complex I RET, either beneficial or detrimental, can be determined by the timing and quantity of ROS production. In this article we review the role of site-specific ROS production at complex I in the contexts of pathology and physiologic signaling.

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