bims-misrem 2020-08-30 papers

Curr Opin Physiol. 2019 Aug;10 96-101

Precision remodeling: how exercise improves mitochondrial quality in myofibers.

The profound energetic demand of prolonged exercise imposed upon skeletal muscle and the heart is met by oxidation of substrate within mitochondria. As such, several coordinated events are initiated in order to maintain mitochondria, collectively known as mitochondrial quality control. In this review, we discuss how mitochondrial quality control functions to maintain the integrity of the reticulum and energy production in response to prolonged exercise, as well as the relevant signaling events that dictate these responses. Based upon the prevailing data in the field, we propose a model where exercise-mediated quality control may be chiefly regulated through local mechanisms, thus allowing for the remarkable precision in mitochondrial quality control events.

Keywords: exercise; mitochondria; mitophagy; muscle; myofiber; quality control

DOI: https://doi.org/10.1016/j.cophys.2019.05.005

Am J Physiol Endocrinol Metab. 2020 Aug 24.

Transcription Factor EB (TFEB): new metabolic coordinators mediating adaptive responses to exercise in skeletal muscle?

Greg Robert Markby, Kei Sakamoto.

In response to the increased energy demands of contractions, skeletal muscle adapts remarkably well through acutely regulating metabolic pathways to maintain energy balance and in the longer term by regulating metabolic reprogramming such as remodeling and expanding the mitochondrial network. This long-term adaptive response involves modulation of gene expression at least partly through the regulation of specific transcription factors and transcriptional coactivators. The AMP-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor-γ co-activator 1a (PGC1a) pathway has long been known to orchestrate contraction-mediated adaptive responses, although AMPK-/PGC1a-independent pathways have also been proposed. Transcription factor EB (TFEB) and TFE3, known as important regulators of lysosomal biogenesis and autophagic processes, have emerged as new metabolic coordinators. The activity of TFEB/TFE3 is regulated through post-translational modifications (i.e. phosphorylation) and spatial organization. Under nutrient/energy stress, TFEB/TFE3 get dephosphorylated and translocate to the nucleus where they activate transcription of their target genes. It has recently been reported that exercise promotes nuclear translocation and activation of TFEB/TFE3 in mouse skeletal muscle through the Ca2+-stimulated protein phosphatase calcineurin. Skeletal muscle-specific ablation of TFEB exhibits impaired glucose homeostasis and mitochondrial biogenesis with reduced metabolic flexibility during exercise, and global TFE3 depletion results in diminished endurance and abolished exercise-induced metabolic benefits. Transcriptomic analysis of the muscle-specific TFEB-null mice has demonstrated that TFEB regulates the expression of genes involved in glucose metabolism and mitochondrial homeostasis. This review aims to summarize and discuss emerging roles for TFEB/TFE3 in metabolic and adaptive responses to exercise/contractile activity in skeletal muscle.

Keywords: AMPK; PGC1a; calcineurin; mTOR

DOI: https://doi.org/10.1152/ajpendo.00339.2020

Sci Adv. 2020 Jul;6(29): eabb9614

Beyond the cell factory: Homeostatic regulation of and by the UPRER.

Melissa G Metcalf, Ryo Higuchi-Sanabria, Gilberto Garcia, C Kimberly Tsui, Andrew Dillin.

The endoplasmic reticulum (ER) is commonly referred to as the factory of the cell, as it is responsible for a large amount of protein and lipid synthesis. As a membrane-bound organelle, the ER has a distinct environment that is ideal for its functions in synthesizing these primary cellular components. Many different quality control machineries exist to maintain ER stability under the stresses associated with synthesizing, folding, and modifying complex proteins and lipids. The best understood of these mechanisms is the unfolded protein response of the ER (UPRER), in which transmembrane proteins serve as sensors, which trigger a coordinated transcriptional response of genes dedicated for mitigating the stress. As the name suggests, the UPRER is most well described as a functional response to protein misfolding stress. Here, we focus on recent findings and emerging themes in additional roles of the UPRER outside of protein homeostasis, including lipid homeostasis, autophagy, apoptosis, and immunity.

DOI: https://doi.org/10.1126/sciadv.abb9614

Biochim Biophys Acta Mol Basis Dis. 2020 Aug 19. pii: S0925-4439(20)30283-0. [Epub ahead of print] 165935

Alteration of mitochondrial supercomplexes assembly in metabolic diseases.

I Ramírez-Camacho, W R García-Niño, M Flores-García, J Pedraza-Chaverri, C Zazueta.

Deregulation of nutrient, hormonal, or neuronal signaling produces metabolic alterations that result in increased mitochondrial reactive oxygen species (ROS) production. The associations of the mitochondrial respiratory chain components into supercomplexes could have pathophysiological relevance in metabolic diseases, as supramolecular arrangements, by sustaining a high electron transport rate, might prevent ROS generation. In this review, the relationship between mitochondrial dysfunction and supercomplex arrangement of the mitochondrial respiratory chain components in obesity, insulin resistance, hepatic steatosis and diabetes mellitus is summarized and discussed.

Keywords: Insulin resistance; Liver; Obesity; Respiratory supercomplexes; T2DM

DOI: https://doi.org/10.1016/j.bbadis.2020.165935

Proc Natl Acad Sci U S A. 2020 Aug 26. pii: 202000643. [Epub ahead of print]

Transcriptome-wide analysis of PGC-1α-binding RNAs identifies genes linked to glucagon metabolic action.

Clint D J Tavares, Stefan Aigner, Kfir Sharabi, Shashank Sathe, Beste Mutlu, Gene W Yeo, Pere Puigserver.

The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a transcriptional coactivator that controls expression of metabolic/energetic genes, programming cellular responses to nutrient and environmental adaptations such as fasting, cold, or exercise. Unlike other coactivators, PGC-1α contains protein domains involved in RNA regulation such as serine/arginine (SR) and RNA recognition motifs (RRMs). However, the RNA targets of PGC-1α and how they pertain to metabolism are unknown. To address this, we performed enhanced ultraviolet (UV) cross-linking and immunoprecipitation followed by sequencing (eCLIP-seq) in primary hepatocytes induced with glucagon. A large fraction of RNAs bound to PGC-1α were intronic sequences of genes involved in transcriptional, signaling, or metabolic function linked to glucagon and fasting responses, but were not the canonical direct transcriptional PGC-1α targets such as OXPHOS or gluconeogenic genes. Among the top-scoring RNA sequences bound to PGC-1α were Foxo1, Camk1δ, Per1, Klf15, Pln4, Cluh, Trpc5, Gfra1, and Slc25a25 PGC-1α depletion decreased a fraction of these glucagon-induced messenger RNA (mRNA) transcript levels. Importantly, knockdown of several of these genes affected glucagon-dependent glucose production, a PGC-1α-regulated metabolic pathway. These studies show that PGC-1α binds to intronic RNA sequences, some of them controlling transcript levels associated with glucagon action.

Keywords: PGC-1α; RNA binding; glucagon; liver; mitochondria

DOI: https://doi.org/10.1073/pnas.2000643117

EMBO Rep. 2020 Aug 27. e50964

Mitochondrial transplantation-a possible therapeutic for mitochondrial dysfunction?: Mitochondrial transfer is a potential cure for many diseases but proof of efficacy and safety is still lacking.

Robert N Lightowlers, Zofia Ma Chrzanowska-Lightowlers, Oliver M Russell.

Transplantation of functional mitochondria directly into defective cells is a novel approach that has recently caught the attention of scientists and the general public alike. Could this be too good to be true?

DOI: https://doi.org/10.15252/embr.202050964