NNT Regulation of Redox Homeostasis Supports Mitochondrial Metabolism and Lung Tumorigenesis

Carcinogenesis is a multi-step process that refers to transformation of a normal cell into a tumoral neoplastic cell. The mechanisms that promote tumor initiation, promotion and progression are varied, complex and remain to be understood. Studies have highlighted the involvement of oncogenic mutations, genomic instability and epigenetic alterations as well as metabolic reprogramming, in different processes of oncogenesis. However, the underlying mechanisms still have to be clarified. Mitochondria are central organelles at the crossroad of various energetic metabolisms. In addition to their pivotal roles in bioenergetic metabolism, they control redox homeostasis, biosynthesis of macromolecules and apoptotic signals, all of which are linked to carcinogenesis. In the present review, we discuss how mitochondria contribute to the initiation of carcinogenesis through gene mutations and production of oncometabolites, and how they promote tumor progression through the control of metabolic reprogramming and mitochondrial dynamics. Finally, we present mitochondrial metabolism as a promising target for the development of novel therapeutic strategies.

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Crosstalk between mitochondrial metabolism and oxidoreductive homeostasis: a new perspective for understanding the effects of bioactive dietary compounds

Nutrition Research Reviews ◽

10.1017/s0954422419000210 ◽

2019 ◽

Vol 33 (1) ◽

pp. 90-101 ◽

Cited By ~ 1

Author(s):

Mariangela Di Giacomo ◽

Vincenzo Zara ◽

Paolo Bergamo ◽

Alessandra Ferramosca

Keyword(s):

Biological Effects ◽

Redox Homeostasis ◽

Natural Compounds ◽

Redox Status ◽

Mitochondrial Metabolism ◽

Functional Link ◽

Cellular Processes ◽

New Therapeutic Approaches ◽

Mitochondrial Functions ◽

New Perspective

AbstractMitochondria play an important role in a number of fundamental cellular processes, including energy production, biosynthetic pathways and cellular oxidoreductive homeostasis (redox status), and their dysfunction can lead to numerous pathophysiological consequences. As the biochemical mechanisms orchestrating mitochondrial metabolism and redox homeostasis are functionally linked, mitochondria have been identified as a potential therapeutic target. Consequently, considerable effort has been made to evaluate the efficacy of natural compounds that modulate mitochondrial function. Molecules produced by plants (for example, polyphenols and isothiocyanates) have been shown to modulate mitochondrial metabolism/biogenesis and redox status; however, despite the existence of a functional link, few studies have considered the combined efficacy of these mitochondrial functions. The present review provides a complete overview of the molecular pathways involved in modulating mitochondrial metabolism/biogenesis and redox status. Crosstalk between these critical mechanisms is also discussed, whilst major data from the literature regarding their antioxidant abilities are described and critically analysed. We also provide a summary of recent evidence regarding the ability of several plant-derived compounds to target these mitochondrial functions. An in-depth understanding of the functional link between mitochondrial metabolism/biogenesis and redox status could facilitate the analysis of the biological effects of natural compounds as well as the development of new therapeutic approaches.

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Natural genetic variation screen in Drosophila identifies Wnt signaling, mitochondrial metabolism, and redox homeostasis genes as modifiers of apoptosis

10.1101/670075 ◽

2019 ◽

Author(s):

Rebecca A.S. Palu ◽

Elaine Ong ◽

Kaitlyn Stevens ◽

Shani Chung ◽

Katie G. Owings ◽

...

Keyword(s):

Genetic Variation ◽

Wnt Signaling ◽

Redox Homeostasis ◽

Enrichment Analysis ◽

Mitochondrial Metabolism ◽

Gene Set Enrichment Analysis ◽

Gene Set Enrichment ◽

Natural Genetic Variation ◽

Effective Diagnosis ◽

The Impact

ABSTRACTApoptosis is the primary cause of degeneration in a number of neuronal, muscular, and metabolic disorders. These diseases are subject to a great deal of phenotypic heterogeneity in patient populations, primarily due to differences in genetic variation between individuals. This creates a barrier to effective diagnosis and treatment. Understanding how genetic variation influences apoptosis could lead to the development of new therapeutics and better personalized treatment approaches. In this study, we examine the impact of the natural genetic variation in the Drosophila Genetic Reference Panel (DGRP) on two models of apoptosis-induced retinal degeneration: overexpression of p53 or reaper (rpr). We identify a number of known apoptotic, neural, and developmental genes as candidate modifiers of degeneration. We also use Gene Set Enrichment Analysis (GSEA) to identify pathways that harbor genetic variation that impact these apoptosis models, including Wnt signaling, mitochondrial metabolism, and redox homeostasis. Finally, we demonstrate that many of these candidates have a functional effect on apoptosis and degeneration. These studies provide a number of avenues for modifying genes and pathways of apoptosis-related disease.

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Bmal1 integrates mitochondrial metabolism and macrophage activation

10.1101/2019.12.20.884429 ◽

2019 ◽

Author(s):

Ryan K. Alexander ◽

Yae-Huei Liou ◽

Nelson H. Knudsen ◽

Kyle A. Starost ◽

Chuanrui Xu ◽

...

Keyword(s):

Immune Cell ◽

Inflammatory Diseases ◽

Redox Homeostasis ◽

Tumor Burden ◽

Mitochondrial Metabolism ◽

Metabolic Reprogramming ◽

Dimethyl Malonate ◽

Melanoma Tumor ◽

Immunosuppressive Tumor Microenvironment ◽

Regulatory Loop

ABSTRACTMetabolic pathways and inflammatory processes are under circadian regulation. While rhythmic immune cell recruitment is known to impact infection outcomes, whether the circadian clock modulates immunometabolism remains unclear. We find the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-γ/lipopolysaccharide (M1) and tumor conditioned medium, to maintain mitochondrial metabolism under these metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial ROS production and Hif-1α-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, the aberrant Hif-1α activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, while administrating an SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint integrating macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1α regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.

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The Atrophic Effect of 1,25(OH)2 Vitamin D3 (Calcitriol) on C2C12 Myotubes Depends on Oxidative Stress

Antioxidants ◽

10.3390/antiox10121980 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1980

Author(s):

Tommaso Raiteri ◽

Ivan Zaggia ◽

Simone Reano ◽

Andrea Scircoli ◽

Laura Salvadori ◽

...

Keyword(s):

Skeletal Muscle ◽

Redox Homeostasis ◽

Antioxidant Properties ◽

Mitochondrial Metabolism ◽

C2c12 Myotubes ◽

Ros Production ◽

Muscle Loss ◽

Mitochondrial Functions ◽

Skeletal Muscle Loss ◽

The Impact

Dysfunctional mitochondrial metabolism has been linked to skeletal muscle loss in several physio-pathological states. Although it has been reported that vitamin D (VD) supports cellular redox homeostasis by maintaining normal mitochondrial functions, and VD deficiency often occurs in conditions associated with skeletal muscle loss, the efficacy of VD supplementation to overcome muscle wasting is debated. Investigations on the direct effects of VD metabolites on skeletal muscle using C2C12 myotubes have revealed an unexpected pro-atrophic activity of calcitriol (1,25VD), while its upstream metabolites cholecalciferol (VD3) and calcidiol (25VD) have anti-atrophic effects. Here, we investigated if the atrophic effects of 1,25VD on myotubes depend on its activity on mitochondrial metabolism. The impact of 1,25VD and its upstream metabolites VD3 and 25VD on mitochondria dynamics and the activity of C2C12 myotubes was evaluated by measuring mitochondrial content, architecture, metabolism, and reactive oxygen species (ROS) production. We found that 1,25VD induces atrophy through protein kinase C (PKC)-mediated ROS production, mainly of extramitochondrial origin. Consistent with this, cotreatment with the antioxidant N-acetylcysteine (NAC), but not with the mitochondria-specific antioxidant mitoTEMPO, was sufficient to blunt the atrophic activity of 1,25VD. In contrast, VD3 and 25VD have antioxidant properties, suggesting that the efficacy of VD supplementation might result from the balance between atrophic pro-oxidant (1,25VD) and protective antioxidant (VD3 and 25VD) metabolites.

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Abstract 3596: Short-term effect of nose-only cigarette smoke exposure on redox homeostasis and mitochondrial metabolism in mice.

10.1158/1538-7445.am2013-3596 ◽

2013 ◽

Author(s):

Haider Raza ◽

Annie John ◽

Abderrahim Nemmar

Keyword(s):

Cigarette Smoke ◽

Redox Homeostasis ◽

Smoke Exposure ◽

Term Effect ◽

Mitochondrial Metabolism ◽

Cigarette Smoke Exposure ◽

Short Term ◽

Short Term Effect

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The Mitochondrial Citrate Carrier (SLC25A1) Sustains Redox Homeostasis and Mitochondrial Metabolism Supporting Radioresistance of Cancer Cells With Tolerance to Cycling Severe Hypoxia

Frontiers in Oncology ◽

10.3389/fonc.2018.00170 ◽

2018 ◽

Vol 8 ◽

Cited By ~ 21

Author(s):

Julian Hlouschek ◽

Christine Hansel ◽

Verena Jendrossek ◽

Johann Matschke

Keyword(s):

Cancer Cells ◽

Redox Homeostasis ◽

Mitochondrial Metabolism ◽

Severe Hypoxia ◽

Citrate Carrier

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Bmal1 integrates mitochondrial metabolism and macrophage activation

eLife ◽

10.7554/elife.54090 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 3

Author(s):

Ryan K Alexander ◽

Yae-Huei Liou ◽

Nelson H Knudsen ◽

Kyle A Starost ◽

Chuanrui Xu ◽

...

Keyword(s):

Immune Cell ◽

Inflammatory Diseases ◽

Redox Homeostasis ◽

Tumor Burden ◽

Mitochondrial Metabolism ◽

Metabolic Reprogramming ◽

Dimethyl Malonate ◽

Melanoma Tumor ◽

Immunosuppressive Tumor Microenvironment ◽

Regulatory Loop

Metabolic pathways and inflammatory processes are under circadian regulation. Rhythmic immune cell recruitment is known to impact infection outcomes, but whether the circadian clock modulates immunometabolism remains unclear. We find that the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-γ/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial production of reactive oxygen species as well as Hif-1α-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, aberrant Hif-1α activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, whereas administering the SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint that integrates macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1α regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.

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