Mitochondrial Phosphopantetheinylation is Required for Oxidative Function.

Sub-cellular compartmentalization of metabolism has important implications for the local production of metabolites and redox co-factors, as well as pathway regulation. 4'-phosphopantetheinyl (4'PP) groups are essential co-factors derived from coenzyme A and added to target proteins in both the cytoplasm and mitochondria by p hospho p antetheinyl transferase (PPTase) enzymes. Mammals express only one PPTase, thought to localize to the cytoplasm: aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT); raising the question of how mitochondrial proteins are 4'PP-modified. We found that AASDHPPT is required for mitochondrial respiration and oxidative metabolism via the mitochondrial fatty acid synthesis (mtFAS) pathway. Moreover, we discovered that a pool of AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 13 amino acids of the protein. Our data show that mitochondrial localization of AASDHPPT is required to support mtFAS function, and further identify two variants in Aasdhppt that are likely pathogenic in humans.

Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.

Contrary to their well-known functions in nutrient breakdown, mitochondria are also important biosynthetic hubs and express an evolutionarily conserved mitochondrial fatty acid synthesis (mtFAS) pathway. mtFAS builds lipoic acid and longer saturated fatty acids, but its exact products, their ultimate destination in cells, and the cellular significance of the pathway are all active research questions. Moreover, why mitochondria need mtFAS despite their well-defined ability to import fatty acids is still unclear. The identification of patients with inborn errors of metabolism in mtFAS genes has sparked fresh research interest in the pathway. New mammalian models have provided insights into how mtFAS coordinates many aspects of oxidative mitochondrial metabolism and raise questions about its role in diseases such as obesity, diabetes, and heart failure. In this review, we discuss the products of mtFAS, their function, and the consequences of mtFAS impairment across models and in metabolic disease.

CCN2 participates in overload-induced skeletal muscle hypertrophy.

The regulation of skeletal muscle growth following pro-hypertrophic stimuli requires a coordinated response by different cell types that leads to extracellular matrix (ECM) remodeling and increases in muscle cross-sectional area. Indeed, matricellular proteins serve a key role as communication vehicles that facilitate the propagation of signaling stimuli required for muscle adaptation to environmental challenges. We found that the matricellular protein cellular communication network factor 2 (CCN2), also known as connective tissue growth factor (CTGF), is induced during a time course of overload-driven skeletal muscle hypertrophy in mice. To elucidate the role of CCN2 in mediating the hypertrophic response, we utilized genetically engineered mouse models for myofiber-specific CCN2 gain- and loss-of-function and then examined their response to mechanical stimuli through muscle overload. Interestingly, myofiber-specific deletion of CCN2 blunted muscle's hypertrophic response to overload without interfering with ECM deposition. On the other hand, when in excess through transgenic CCN2 overexpression, CCN2 was efficient in promoting overload-induced aberrant ECM accumulation without affecting myofiber growth. Altogether, our genetic approaches highlighted independent ECM and myofiber stress adaptation responses, and positioned CCN2 as a central mediator of both. Mechanistically, CCN2 acts by regulating focal adhesion kinase (FAK) mediated transduction of overload-induced extracellular signals, including interleukin 6 (IL6), and their regulatory impact on global protein synthesis in skeletal muscle. Overall, our study highlights the contribution of muscle-derived extracellular matrix factor CCN2 for proper hypertrophic muscle growth.

Cardiac-derived TGF-ß1 confers resistance to diet-induced obesity through the regulation of adipocyte size and function.

Regulation of organismal homeostasis in response to nutrient availability is a vital physiological process that involves inter-organ communication. Understanding the mechanisms controlling systemic cross-talk for the maintenance of metabolic health is critical to counteract diet-induced obesity. Here, we show that cardiac-derived transforming growth factor beta 1 (TGF-ß1) protects against weight gain and glucose intolerance in mice subjected to high-fat diet. Secretion of TGF-ß1 by cardiomyocytes correlates with the bioavailability of this factor in circulation. TGF-ß1 prevents adipose tissue inflammation independent of body mass and glucose metabolism phenotypes, indicating protection from adipocyte dysfunction-driven immune cell recruitment. TGF-ß1 alters the gene expression programs in white adipocytes, favoring their fatty acid oxidation and consequently increasing their mitochondrial oxygen consumption rates. Ultimately, subcutaneous and visceral white adipose tissue from cadiac-specific TGF-ß1 transgenic mice fail to undergo cellular hypertrophy, leading to reduced overall adiposity during high-fat feeding. Thus, TGF-ß1 is a critical mediator of heart-fat communication for the regulation of systemic metabolism.

ERK1/2: An Integrator of Signals That Alters Cardiac Homeostasis and Growth.

Integration of cellular responses to extracellular cues is essential for cell survival and adaptation to stress. Extracellular signal-regulated kinase (ERK) 1 and 2 serve an evolutionarily conserved role for intracellular signal transduction that proved critical for cardiomyocyte homeostasis and cardiac stress responses. Considering the importance of ERK1/2 in the heart, understanding how these kinases operate in both normal and disease states is critical. Here, we review the complexity of upstream and downstream signals that govern ERK1/2-dependent regulation of cardiac structure and function. Particular emphasis is given to cardiomyocyte hypertrophy as an outcome of ERK1/2 activation regulation in the heart.

Paracardial fat remodeling affects systemic metabolism through alcohol dehydrogenase 1.

The relationship between adiposity and metabolic health is well established. However, very little is known about the fat depot, known as paracardial fat (pCF), located superior to and surrounding the heart. Here, we show that pCF remodels with aging and a high-fat diet and that the size and function of this depot are controlled by alcohol dehydrogenase 1 (ADH1), an enzyme that oxidizes retinol into retinaldehyde. Elderly individuals and individuals with obesity have low ADH1 expression in pCF, and in mice, genetic ablation of Adh1 is sufficient to drive pCF accumulation, dysfunction, and global impairments in metabolic flexibility. Metabolomics analysis revealed that pCF controlled the levels of circulating metabolites affecting fatty acid biosynthesis. Also, surgical removal of the pCF depot was sufficient to rescue the impairments in cardiometabolic flexibility and fitness observed in Adh1-deficient mice. Furthermore, treatment with retinaldehyde prevented pCF remodeling in these animals. Mechanistically, we found that the ADH1/retinaldehyde pathway works by driving PGC-1α nuclear translocation and promoting mitochondrial fusion and biogenesis in the pCF depot. Together, these data demonstrate that pCF is a critical regulator of cardiometabolic fitness and that retinaldehyde and its generating enzyme ADH1 act as critical regulators of adipocyte remodeling in the pCF depot.

Epitranscriptomics in the Heart: a Focus on m6A.

PURPOSE OF REVIEW: Post-transcriptional modifications are key regulators of gene expression that allow the cell to respond to environmental stimuli. The most abundant internal mRNA modification is N6-methyladenosine (m6A), which has been shown to be involved in the regulation of RNA splicing, localization, translation, and decay. It has also been implicated in a wide range of diseases, and here, we review recent evidence of m6A's involvement in cardiac pathologies and processes. RECENT FINDINGS: Studies have primarily relied on gain and loss of function models for the enzymes responsible for adding and removing the m6A modification. Results have revealed a multifaceted role for m6A in the heart's response to myocardial infarction, pressure overload, and ischemia/reperfusion injuries. Genome-wide analyses of mRNAs that are differentially methylated during cardiac stress have highlighted the importance of m6A in regulating the translation of specific categories of transcripts implicated in pathways such as calcium handling, cell growth, autophagy, and adrenergic signaling in cardiomyocytes. Regulation of gene expression by m6A is critical for cardiomyocyte homeostasis and stress responses, suggesting a key role for this modification in cardiac pathophysiology.