The dynamics of mitochondrial-linked gene expression among tissues and life stages in two contrasting strains of laying hens

The cellular energy metabolism is one of the most conserved processes, as it is present in all living organisms. Mitochondria are providing the eukaryotic cell with energy and thus their genome and gene expression has been of broad interest for a long time. Mitochondrial gene expression changes under different conditions and is regulated by genes encoded in the nucleus of the cell. In this context, little is known about non-model organisms and we provide the first large-scaled gene expression analysis of mitochondrial-linked genes in laying hens. We analysed 28 mitochondrial and nuclear genes in 100 individuals in the context of five life-stages and strain differences among five tissues. Our study showed that mitochondrial gene expression increases during the productive life span, and reacts tissue and strain specific. In addition, the strains react different to potential increased oxidative stress, resulting from the increase in mitochondrial gene expression. The results suggest that the cellular energy metabolism as part of a complex regulatory system is strongly affected by the productive life span in laying hens and thus partly comparable to model organisms. This study provides a starting point for further analyses in this field on non-model organisms, especially in laying-hens.

Safety of Dietary Guanidinoacetic Acid: A Villain of a Good Guy?

Guanidinoacetic acid (GAA) is a natural amino acid derivative that is well-recognized for its central role in the biosynthesis of creatine, an essential compound involved in cellular energy metabolism. GAA (also known as glycocyamine or betacyamine) has been investigated as an energy-boosting dietary supplement in humans for more than 70 years. GAA is suggested to effectively increase low levels of tissue creatine and improve clinical features of cardiometabolic and neurological diseases, with GAA often outcompeting traditional bioenergetics agents in maintaining ATP status during stress. This perhaps happens due to a favorable delivery of GAA through specific membrane transporters (such as SLC6A6 and SLC6A13), previously dismissed as un-targetable carriers by other therapeutics, including creatine. The promising effects of dietary GAA might be countered by side-effects and possible toxicity. Animal studies reported neurotoxic and pro-oxidant effects of GAA accumulation, with exogenous GAA also appearing to increase methylation demand and circulating homocysteine, implying a possible metabolic burden of GAA intervention. This mini-review summarizes GAA toxicity evidence in human nutrition and outlines functional GAA safety through benefit-risk assessment and multi-criteria decision analysis.

LIPID DROPLET SIGNALING IN METABOLIC HEALTH AND AGING

Lipid droplets (LDs) are neutral lipid rich organelles involved in lipid storage, fatty acid trafficking, and signaling. Emerging evidence from our laboratory and others suggests that the specific LD resident proteins couple/uncouple cells and tissues from inflammation and metabolic dysfunction. However, the mechanism by which LD proteins influences these critical pathways remains unknown. We will present data delving into the role of LD proteins Perilipin (PLIN) 2 and 5 in balancing cellular energy metabolism, mitochondrial function, and inflammation. Data will be presented defining novel mechanisms through which PLIN2 orchestrates eicosanoid production as a means to promote inflammation. We will contrast these findings to PLIN5, which uncouples LD accumulation from metabolic dysfunction and inflammation, in part due to its promotion of SIRT1 signaling. Overall, these studies will highlight a crucial role of LD metabolism and signaling in regulating cellular energy homeostatic processes known to be key players in governing healthspan.

Targeting Mitochondria in Diabetes

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy metabolism, are involved in the mechanisms of IR and T2D. Mitochondrial function is affected by insulin resistance in different tissues, among which skeletal muscle and liver have the highest impact on whole-body glucose homeostasis. This review focuses on human studies that assess mitochondrial function in liver, muscle and blood cells in the context of T2D. Furthermore, different interventions targeting mitochondria in IR and T2D are listed, with a selection of studies using respirometry as a measure of mitochondrial function, for better data comparison. Altogether, mitochondrial respiratory capacity appears to be a metabolic indicator since it decreases as the disease progresses but increases after lifestyle (exercise) and pharmacological interventions, together with the improvement in metabolic health. Finally, novel therapeutics developed to target mitochondria have potential for a more integrative therapeutic approach, treating both causative and secondary defects of diabetes.

The RNA-binding protein RBP42 regulates cellular energy metabolism in mammalian-infective Trypanosoma brucei

RNA-binding proteins are key players in coordinated post-transcriptional regulation of functionally related genes, defined as RNA regulons. RNA regulons play particularly critical roles in parasitic trypanosomes, which exhibit unregulated co-transcription of long arrays of unrelated genes. In this report, we present a systematic analysis of an essential RNA-binding protein, RBP42, in the mammalian-infective slender bloodstream form of African trypanosome, and we show that RBP42 is a key regulator of parasite’s central carbon and energy metabolism. Using individual-nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP) to identify genome-wide RBP42-RNA interactions, we show that RBP42 preferentially binds within the coding region of mRNAs encoding core metabolic enzymes. Using global quantitative transcriptomic and proteomic analyses, we also show that loss of RBP42 reduces the abundance of target mRNA-encoded proteins, but not target mRNA, suggesting a plausible role of RBP42 as a positive regulator of target mRNA translation. Analysis reveals significant changes in central carbon metabolic intermediates following loss of RBP42, further supporting its critical role in cellular energy metabolism.

Pyruvate dehydrogenase kinases (PDKs): an overview toward clinical applications

Pyruvate dehydrogenase kinase (PDK) can regulate the catalytic activity of pyruvate decarboxylation oxidation via the mitochondrial pyruvate dehydrogenase complex, and it further links glycolysis with the tricarboxylic acid cycle and ATP generation. This review seeks to elucidate the regulation of PDK activity in different species, mainly mammals, and the role of PDK inhibitors in preventing increased blood glucose, reducing injury caused by myocardial ischemia, and inducing apoptosis of tumor cells. Regulations of PDKs expression or activity represent a very promising approach for treatment of metabolic diseases including diabetes, heart failure, and cancer. The future research and development could be more focused on the biochemical understanding of the diseases, which would help understand the cellular energy metabolism and its regulation by pharmacological effectors of PDKs.

Prognosis of cellular energy metabolism shifts in adolescents with community-acquired pneumonia

Pneumonia is one of the most severe respiratory pathology forms in children, which contributes significantly to infant mortality. The high risk of chronic bronchopulmonary process and child`s disability, in case of severe and complicated disease, requires careful pathophysiological change's analysis in community-acquired pneumonia (CAP) in children. In particular, for the prediction of these disorders in children with CAP are important the dysmetabolic phenomena study and the specific approaches development. The immediate aim of this work is to study the cellular energy metabolism (CEM) features and to develop approaches for the early bioenergetic disorders diagnostics in conditions of community-acquired pneumonia in adolescents.The aim of the study is to develop approaches for the early diagnosis of shifts in energy metabolism in children aged 14-18 years with CAP. An examination of 41 children aged 14-16 years with the definition of CEM indicators was conducted in order to develop an approach for predicting CEM disorders in community-acquired pneumonia using the method of logistic regression. A logistic regression method was used to develop a method for predicting CEM disorders in children with CAP. The characteristics of CEM in children with CAP were determined. A decrease in the succinate dehydrogenase activity and an increase in the lactate dehydrogenase / succinate dehydrogenase ratio in children with CAP relative to the reference parameters were observed, which indicated an inhibition of the anaerobic energy synthesis pathway. Two mathematical models for predicting CEM disorders in CAP based on logistic regression equations were proposed. The first mathematical model consisted of social and health characteristics and of pneumonia clinical course characteristics. In ROC analysis the area under the curve (AUC) was 0.82, diagnostic specificity – 71%, diagnostic sensitivity – 90%. The second model included only hematological parameters, AUC – 0.78, diagnostic specificity – 69%, diagnostic sensitivity – 81%. Thus, changes in CEM in children with CAP aged 14 – 18 years have been established. Two methods for predicting disorders of CEM in children with CAP have been developed, which can be applied to optimize the treatment of children with CAP aged 14-18 years.

The PPR domain of mitochondrial RNA polymerase is a ribonuclease required for mtDNA replication

Mitochondrial DNA (mtDNA) replication and transcription are of paramount importance to cellular energy metabolism. Mitochondrial RNA polymerase (POLRMT) is thought to be the primase for mtDNA replication. However, it is unclear how POLRMT, which normally transcribes long polycistronic RNAs, can produce short RNA oligos to initiate mtDNA replication. Here we show that the PPR domain of Drosophila POLRMT is a 3’ to 5’ exoribonuclease. The exoribonuclease activity is indispensable for POLRMT to synthesize short RNA oligos and to prime DNA replication in vitro. An exoribonuclease deficient POLRMT, POLRMTE423P partially restores mitochondrial transcription but fails to support mtDNA replication when expressed in POLRMT mutant background, indicating that the exoribonuclease activity is necessary for mtDNA replication. Overexpression of POLRMTE423P in adult flies leads to severe neuromuscular defects and a marked increase of mtDNA transcripts errors, suggesting that exoribonuclease activity may contribute to the proofreading of mtDNA transcription. PPR domain of human POLRMT also has exoribonuclease activity, indicating evolutionarily conserved roles of PPR domain in mitochondrial DNA and RNA metabolism.