Oxidative Stress, Mitochondrial Function and Adaptation to Exercise: New Perspectives in Nutrition

Cells have the ability to adapt to stressful environments as a part of their evolution. Physical exercise induces an increase of a demand for energy that must be met by mitochondria as the main (ATP) provider. However, this process leads to the increase of free radicals and the so-called reactive oxygen species (ROS), which are necessary for the maintenance of cell signaling and homeostasis. In addition, mitochondrial biogenesis is influenced by exercise in continuous crosstalk between the mitochondria and the nuclear genome. Excessive workloads may induce severe mitochondrial stress, resulting in oxidative damage. In this regard, the objective of this work was to provide a general overview of the molecular mechanisms involved in mitochondrial adaptation during exercise and to understand if some nutrients such as antioxidants may be implicated in blunt adaptation and/or an impact on the performance of exercise by different means.

Mitochondrial Metabolism in Melanoma

Melanoma and its associated alterations in cellular pathways have been growing areas of interest in research, especially as specific biological pathways are being elucidated. Some of these alterations include changes in the mitochondrial metabolism in melanoma. Many mitochondrial metabolic changes lead to differences in the survivability of cancer cells and confer resistance to targeted therapies. While extensive work has gone into characterizing mechanisms of resistance, the role of mitochondrial adaptation as a mode of resistance is not completely understood. In this review, we wish to explore mitochondrial metabolism in melanoma and how it impacts modes of resistance. There are several genes that play a major role in melanoma mitochondrial metabolism which require a full understanding to optimally target melanoma. These include BRAF, CRAF, SOX2, MCL1, TRAP1, RHOA, SRF, SIRT3, PTEN, and AKT1. We will be discussing the role of these genes in melanoma in greater detail. An enhanced understanding of mitochondrial metabolism and these modes of resistance may result in novel combinatorial and sequential therapies that may lead to greater therapeutic benefit.

Nrf2 is a central regulator of the metabolic landscape in macrophages and finetunes their inflammatory response

To overcome oxidative, inflammatory, and metabolic stress, cells have evolved networks of cytoprotective proteins controlled by nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator the Kelch-like ECH associated protein 1 (Keap1). Here, we used high-resolution mass-spectrometry to characterize the proteomes of macrophages with genetically altered Nrf2 status. Our analysis revealed significant differences among the genotypes in cellular metabolism and redox homeostasis, which we validated with respirometry and metabolomics, as well as in anti-viral immune pathways and the cell cycle. Nrf2 status significantly affected the proteome following lipopolysaccharide (LPS) stimulation, with alterations in redox, carbohydrate and lipid metabolism, and innate immunity observed. Of note, Nrf2 activation was found to promote mitochondrial fusion in inflammatory macrophages. The Keap1 inhibitor, 4-octyl itaconate (4-OI), a derivative of the mitochondrial immunometabolite itaconate, remodeled the inflammatory macrophage proteome, increasing redox and suppressing anti-viral immune effectors in a Nrf2-dependent manner. These data suggest that Nrf2 activation facilitates metabolic reprogramming and mitochondrial adaptation, and finetunes the innate immune response in macrophages.

Severe Disease Activity and Liver Fibrosis Are Associated With a Lack of Hepatic Mitochondrial Adaptation in Patients With NASH

Dysfunctional mitochondrial function is believed to play a vital role in the progression of nonalcoholic steatohepatitis (NASH) to advanced fibrosis and cirrhosis. However, most evidence arises from animal models while there is limited data in humans. The characteristic histological finding of NASH is hepatocellular injury with ballooning and inflammation, often associated with fibrosis in advanced disease. The aim of this study was to assess the role of mitochondrial function (eg, oxidative phosphorylation [OXPHOS] in patients with vs. without NASH and fibrosis. To this end, we recruited 38 patients with NAFLD with risk factors (obesity and/or type 2 diabetes) for NASH (age: 52±12 years; 37% male; BMI: 39.6±8.5 kg/m2; HbA1c: 6.8±1.4%) in whom we assessed mitochondrial respiration and also performed measurements of insulin resistance (IR). Tissue was obtained by either a Tru-cut percutaneous liver biopsy (n=26) or a wedge biopsy during bariatric surgery (n=12). After tissue was separated for histological diagnosis, small liver samples (2–4 mg) were processed to quantify OXPHOS by measuring the mitochondrial oxygen consumption rate in individual complexes of mitochondria, expressed as pmol×mg wet weight-1×s-1, using high-resolution respirometry, Oxygraph-2k. Based on liver histology, patients with NASH (n=18) compared to without NASH (n=20), had worse hyperinsulinemia and HOMA-IR (25.2±10.5 vs 14.9± 6.7 µU/ml and 8.9±4.3 vs. 4.9±2.9 mg/dl × µU/ml, respectively) and higher OXPHOS (all p<0.05), although well matched for age, BMI, HbA1c and % with diabetes. This was likely an adaptation to IR and higher FFA flux to the liver. We then examined patients based specifically on disease activity, using a combined score of hepatocyte ballooning and inflammation (necroinflammation score [NIS]) and divided as mild (n=16), moderate (n=14) or severe (n=8) NIS (also well matched for relevant clinical parameters). Patients in the moderate vs. mild NIS group disease activity had increased mitochondrial respiration as represented by OXPHOS (45.9±11.8 vs. 31.3±9.8), electron transport chain activity (ETC) (61.0±17.6 vs. 46.4±15.2) and state 3 respiration induced by ADP (20.7±4.9 vs. 16.4±4.6 pmol×mg wet weight-1×s-1; all p<0.05). There was a trend for these parameters to decline in patients with severe vs. moderate disease activity, that was further accentuated when patients with NASH also had clinically significant fibrosis compared to those with mild or no fibrosis (OXPHOS: 37.9±7.8 vs. 49.8±12.5, p=0.04; and ETC: 49.8±13.4 vs. 67.5±16.1, p=0.02). Conclusion: In patients with NASH, there is an early hepatic mitochondrial adaptation to account for the state of more severe insulin resistance in steatohepatitis compared to simple steatosis. This adaptation is impaired when disease activity worsens and is most evident once patients develop steatohepatitis with significant fibrosis.

Investigation of Mitochondrial Adaptations to Modulation of Carbohydrate Supply during Adipogenesis of 3T3-L1 Cells by Targeted 1H-NMR Spectroscopy

(1) Background: White adipose tissue (WAT) is a dynamic and plastic tissue showing high sensitivity to carbohydrate supply. In such a context, the WAT may accordingly modulate its mitochondrial metabolic activity. We previously demonstrated that a partial replacement of glucose by galactose in a culture medium of 3T3-L1 cells leads to a poorer adipogenic yield and improved global mitochondrial health. In the present study, we investigate key mitochondrial metabolic actors reflecting mitochondrial adaptation in response to different carbohydrate supplies. (2) Methods: The metabolome of 3T3-L1 cells was investigated during the differentiation process using different glucose/galactose ratios and by a targeted approach using 1H-NMR (Proton nuclear magnetic resonance) spectroscopy; (3) Results: Our findings indicate a reduction of adipogenic and metabolic overload markers under the low glucose/galactose condition. In addition, a remodeling of the mitochondrial function triggers the secretion of metabolites with signaling and systemic energetical homeostasis functions. Finally, this study also sheds light on a new way to consider the mitochondrial metabolic function by considering noncarbohydrates related pathways reflecting both healthier cellular and mitochondrial adaptation mechanisms; (4) Conclusions: Different carbohydrates supplies induce deep mitochondrial metabolic and function adaptations leading to overall adipocytes function and profile remodeling during the adipogenesis.

The benefits and physiological changes of high intensity interval training

Physical inactivity have been linked with many major non-communicable diseases and as many as 27.5% of adults globally are considered inactive. Physical activity has been proven to be beneficial in the prevention of many chronic diseases and may reduce the risk of premature death. High intensity interval training (HIIT) has been gaining popularity as a time-efficient alternative for regular exercise training. Current studies show that HIIT is more efficient in improving cardiorespiratory fitness, increasing insulin sensitivity and reducing blood pressure than moderate intensity continuous training (MICT). The advantage of HIIT in fat loss compared to MICT is still unclear, but HIIT might be more efficient in the obese population. The effect of HIIT on increasing aerobic fitness could be caused by increase in stroke volume due to the increase in cardiac contractility, capillary density and mitochondrial adaptation. Fat loss during HIIT could be caused by increased fat oxidation and elevated hormones that drive lipolysis and reduce appetite. While vigorous physical activity may transiently increase the risk of cardiac events. The effect of HIIT on increasing aerobic fitness could be caused by increase in stroke volume due to the increase in cardiac contractility, increased of capillary density and mitochondrial adaptation. While fat loss during HIIT could be caused by an increased fat oxidation, elevated hormones that drives lipolysis and reduces appetite. While vigorous physical activity may transiently increase the risk of cardiac event. High intensity interval training is generally safe even in the elderly population and in people with coronary heart disease.