Goldfish Response to Chronic Hypoxia: Mitochondrial Respiration, Fuel Preference and Energy Metabolism

Hypometabolism is a hallmark strategy of hypoxia tolerance. To identify potential mechanisms of metabolic suppression, we have used the goldfish to quantify the effects of chronically low oxygen (4 weeks; 10% air saturation) on mitochondrial respiration capacity and fuel preference. The responses of key enzymes from glycolysis, β-oxidation and the tricarboxylic acid (TCA) cycle, and Na+/K+-ATPase were also monitored in various tissues of this champion of hypoxia tolerance. Results show that mitochondrial respiration of individual tissues depends on oxygen availability as well as metabolic fuel oxidized. All the respiration parameters measured in this study (LEAK, OXPHOS, Respiratory Control Ratio, CCCP-uncoupled, and COX) are affected by hypoxia, at least for one of the metabolic fuels. However, no common pattern of changes in respiration states is observed across tissues, except for the general downregulation of COX that may help metabolic suppression. Hypoxia causes the brain to switch from carbohydrates to lipids, with no clear fuel preference in other tissues. It also downregulates brain Na+/K+-ATPase (40%) and causes widespread tissue-specific effects on glycolysis and beta-oxidation. This study shows that hypoxia-acclimated goldfish mainly promote metabolic suppression by adjusting the glycolytic supply of pyruvate, reducing brain Na+/K+-ATPase, and downregulating COX, most likely decreasing mitochondrial density.

Loss of Mitochondrial Control Impacts Renal Health

Disruption of mitochondrial biosynthesis or dynamics, or loss of control over mitochondrial regulation leads to a significant alteration in fuel preference and metabolic shifts that potentially affect the health of kidney cells. Mitochondria regulate metabolic networks which affect multiple cellular processes. Indeed, mitochondria have established themselves as therapeutic targets in several diseases. The importance of mitochondria in regulating the pathogenesis of several diseases has been recognized, however, there is limited understanding of mitochondrial biology in the kidney. This review provides an overview of mitochondrial dysfunction in kidney diseases. We describe the importance of mitochondria and mitochondrial sirtuins in the regulation of renal metabolic shifts in diverse cells types, and review this loss of control leads to increased cell-to-cell transdifferentiation processes and myofibroblast-metabolic shifts, which affect the pathophysiology of several kidney diseases. In addition, we examine mitochondrial-targeted therapeutic agents that offer potential leads in combating kidney diseases.

Perspective: Ketone Supplementation in Sports—Does It Work?

ABSTRACT Oral ketone supplements have gained popularity in recent years. There is biological rationale for a potential ergogenic effect of this type of supplement, as they might not only alter muscle fuel preference during exercise (and promote glycogen sparing, with potential benefits for endurance performance) but also favor cognition performance during exertion or muscle glycogen synthesis after exercise. However, as discussed in this Perspective, evidence to date does not support a benefit of acute ketone supplementation on sports performance, cognition, or muscle recovery [although further research with long-duration exercise (i.e., >60 min), is needed], and the evidence for chronic supplementation is sparse. In addition, acute intake of ketone supplements might be associated with gastrointestinal symptoms, and further research is warranted on the long-term safety of repeated use of ketone supplements. In summary, there is currently insufficient evidence to support the overall effectiveness of ketone supplements in sports.

A dietary anthocyanin cyanidin-3-O-glucoside binds to PPARs to regulate glucose metabolism and insulin sensitivity in mice

We demonstrate the mechanism by which C3G, a major dietary anthocyanin, regulates energy metabolism and insulin sensitivity. Oral administration of C3G reduced hepatic and plasma triglyceride levels, adiposity, and improved glucose tolerance in mice fed high-fat diet. Hepatic metabolomic analysis revealed that C3G shifted metabolite profiles towards fatty acid oxidation and ketogenesis. C3G increased glucose uptake in HepG2 cells and C2C12 myotubes and induced the rate of hepatic fatty acid oxidation. C3G directly interacted with and activated PPARs, with the highest affinity for PPARα. The ability of C3G to reduce plasma and hepatic triglycerides, glucose tolerance, and adiposity and to induce oxygen consumption and energy expenditure was abrogated in PPARα-deficient mice, suggesting that PPARα is the major target for C3G. These findings demonstrate that the dietary anthocyanin C3G activates PPARs, a master regulators of energy metabolism. C3G is an agonistic ligand of PPARs and stimulates fuel preference to fat.

Abstract 517: Substrate Dependence of Mitochondrial Supercomplex Abundance in Murine Heart

Mitochondrial supercomplexes are prominent in mammalian tissues that have high energy demand. Nevertheless, the mechanisms that regulate supercomplex formation and abundance remain unclear. In this study, we examined how myocardial fuel preference regulated by constitutive changes in phosphofructokinase (PFK) activity in vivo or by differential substrate provision to isolated mitochondria affect mitochondrial supercomplexes. Protein complexes from digitonin-solubilized cardiac mitochondria were resolved by blue-native polyacrylamide gel electrophoresis and were identified by mass spectrometry and immunoblotting to contain Complexes I, III, and IV as well as accessory proteins. Mitochondria from hearts with low PFK activity (Glyco Lo hearts) had higher mitochondrial supercomplex abundance and activity compared with mitochondria from wild-type (WT) or Glyco Hi hearts. Incubation of WT mitochondria with fatty acyl carnitine promoted higher supercomplex formation than did incubation with pyruvate, suggesting that substrate utilization is sufficient to regulate mitochondrial supercomplex abundance. These data are consistent with the hypothesis that mitochondrial supercomplex abundance is regulated in a substrate-dependent manner and suggest that metabolic scenarios favoring fat oxidation may promote supercomplex abundance.

Consumer Preferences for Cooking and Lighting Fuels and Domestic Energy Transition: A Nyeri Town, Kenya, Perspective

Improving access to modern fuels in developing countries is crucial in mitigating unfavorable environmental and health impacts caused by the continued use of traditional fuels. Use of modern fuels lead to improved standards of living and gender equity of women and children. This paper estimates preferences for domestic fuels and reasons thereof by households in urban areas in Nyeri town, Kenya. The study uses Nyeri town micro-data to perform correlation analysis to determine the relationship between fuel preference and domestic energy transition. Transition is considered along three categories of domestic fuels: traditional -firewood and charcoal; transitional fuels- kerosene; modern fuels – Liquefied Petroleum Gas (LPG), biogas, solar and grid electricity. The result findings show that urban residents use traditional, transitional and modern fuels through energy stacking theory with the transition to modern fuels following a consistent pattern. The major reasons for fuel preference were established as fuel convenience, affordability, ease of accessibility and cultural beliefs by 46.5%, 37.2%, 10.5% and 5.8% of the respondents respectively.

Expansion capacity of human muscle progenitor cells differs by age, sex, and metabolic fuel preference

Activation of satellite cells and expansion of the muscle progenitor cell (MPC) population are essential to generate a sufficient number of cells to repair damaged skeletal muscle. Proliferating MPCs have high energetic and biosynthetic material requirements, and the ability to utilize oxidative phosphorylation (OXPHOS) and/or glycolysis may affect expansion capacity of MPCs. In the present study, we investigated the effect of donor age and sex on human (h)MPC expansion capacity and metabolic fuel preference. hMPCs from young and old male and female donors were grown for 408 h (17 days). Percent confluence, live nuclei count, and dead cell count were measured every 24 h. Metabolic phenotype was assessed by glucose uptake, expression of genes related to glycolysis and OXPHOS, and the Seahorse XF24 Phenotype Test Kit during the exponential phase of growth. hMPCs from old male donors had impaired expansion capacity secondary to heightened cell death early in expansion compared with hMPCs from young male donors, an effect not observed in female hMPCs. Age-related differences in metabolism were also sex dependent; markers of OXPHOS were altered in old (vs. young) male hMPCs, whereas markers of metabolism were largely unaffected by age in female hMPCs. For the first time, we identify sex-specific differences in cell death and OXPHOS that contribute to impaired expansion capacity of hMPC cell populations with age.