bims-misrem 2021-09-19 papers

Biochim Biophys Acta Gen Subj. 2021 Sep 11. pii: S0304-4165(21)00170-7. [Epub ahead of print] 130011

Mitochondrial-derived peptides and exercise.

Acute exercise, and in particular aerobic exercise, increases skeletal muscle energy demand causing mitochondrial stress, and mitochondrial-related adaptations which are a hallmark of exercise training. Given that mitochondria are central players in the exercise response, it is imperative that they have networks that can communicate their status both intra- and inter-cellularly. Peptides encoded by short open-reading frames within mitochondrial DNA, mitochondrial-derived peptides (MDPs), have been suggested to form a newly recognised branch of this retrograde signalling cascade that contribute to coordinating the adaptive response to regular exercise. Here we summarise the recent evidence that acute high intensity exercise in humans can increase concentrations of the MDPs humanin and MOTS-c in skeletal muscle and plasma, and speculate on the mechanisms controlling MDP responses to exercise stress. Evidence that exercise training results in chronic changes in MDP expression within tissues and the circulation is conflicting and may depend on the mode, duration, intensity of training plan and participant characteristics. Further research is required to define the effect of these variables on MDPs and to determine whether MDPs other than MOTS-c have exercise mimetic properties. MOTS-c treatment of young and aged mice improves exercise capacity/performance and leads to adaptions that are similar to that of being physically active (weight loss, increased antioxidant capacity and improved insulin sensitivity), however, studies utilising a MOTS-c inactivating genetic variant or combination of exercise + MOTS-c treatment in mice suggest that there are distinct and overlapping pathways through which exercise and MOTS-c evoke metabolic benefits. Overall, MOTS-c, and potentially other MDPs, may be exercise-sensitive myokines and further work is required to define inter- and intra-tissue targets in an exercise context.

Keywords: Cellular signalling; Hormesis; Mitochondria; Muscle; Physical activity; ROS

DOI: https://doi.org/10.1016/j.bbagen.2021.130011

FEBS J. 2021 Sep 12.

Targeting Adaptive Cellular Responses To Mitochondrial Bioenergetic Deficiencies In Human Disease.

Christopher F Bennett, Conor T Ronayne, Pere Puigserver.

Mitochondrial dysfunction is increasingly appreciated as a central contributor to human disease. Oxidative metabolism at the mitochondrial respiratory chain produces ATP and is intricately tied to redox homeostasis and biosynthetic pathways. Metabolic stress arising from genetic mutations in mitochondrial genes and environmental factors such as malnutrition or overnutrition is perceived by the cell and leads to adaptive and maladaptive responses that can underlie pathology. Here, we will outline cellular sensors that react to alterations in energy production, organellar redox, and metabolites stemming from mitochondrial disease (MD) mutations. MD is a heterogenous group of disorders primarily defined by defects in mitochondrial oxidative phosphorylation from nuclear or mitochondrial-encoded gene mutations. Pre-clinical therapies that improve fitness of MD mouse models have been recently identified. Targeting metabolic/energetic deficiencies, maladaptive signaling processes, and hyper-oxygenation of tissues are all strategies aside from direct genetic approaches that hold therapeutic promise. A further mechanistic understanding of these curative processes as well as the identification of novel targets will significantly impact mitochondrial biology and disease research.

Keywords: Mitochondrial dysfunction; hypoxia; mTORC1; metabolism; mitochondrial disease; mitochondrial signaling; oxidative stress; reactive oxygen species; redox homeostasis

DOI: https://doi.org/10.1111/febs.16195

J Biol Chem. 2021 Sep 13. pii: S0021-9258(21)00998-4. [Epub ahead of print] 101196

William T King, Christopher L Axelrod, Elizabeth R M Zunica, Robert C Noland, Gangarao Davuluri, Hisashi Fujioka, Bernard Tandler, Kathryn Pergola, Gerlinda E Hermann, Richard C Rogers, Sandra López-Domènech, Wagner S Dantas, Krisztian Stadler, Charles L Hoppel, John P Kirwan.

Mitochondria undergo continuous cycles of fission and fusion to promote inheritance, regulate quality control, and mitigate organelle stress. More recently, this process of mitochondrial dynamics has been demonstrated to be highly sensitive to nutrient supply, ultimately conferring bioenergetic plasticity to the organelle. However, whether regulators of mitochondrial dynamics play a causative role in nutrient regulation remains unclear. In this study, we generated a cellular loss-of-function model for dynamin-related protein 1 (DRP1), the primary regulator of outer membrane mitochondrial fission. Loss of DRP1 (shDRP1) resulted in extensive ultrastructural and functional remodeling of mitochondria, characterized by pleomorphic enlargement, increased electron density of the matrix, and defective NADH and succinate oxidation. Despite increased mitochondrial size and volume, shDRP1 cells exhibited reduced cellular glucose uptake and mitochondrial fatty acid oxidation. Untargeted transcriptomic profiling revealed severe downregulation of genes required for cellular and mitochondrial calcium homeostasis, inhibition of ATP-stimulated calcium flux, and impaired substrate oxidation stimulated by calcium levels. The insights obtained herein suggest that DRP1 regulates fatty acid oxidation by altering whole-cell and mitochondrial calcium dynamics. These findings are relevant to the targetability of mitochondrial fission and have clinical relevance in the identification of treatments for fission-related pathologies such as hereditary neuropathies, inborn errors in metabolism, cancer, and chronic diseases.

Keywords: calcium signaling; dynamin-related protein 1; mitochondrial dynamics; skeletal muscle; β-oxidation

DOI: https://doi.org/10.1016/j.jbc.2021.101196

FEBS Open Bio. 2021 Sep 12.

Lactate administration does not affect denervation-induced loss of mitochondrial content and muscle mass in mice.

Kenya Takahashi, Yu Kitaoka, Yutaka Matsunaga, Hideo Hatta.

Lactate is considered to be a signaling molecule that induces mitochondrial adaptation and muscle hypertrophy. The purpose of this study was to examine whether lactate administration attenuates denervation-induced loss of mitochondrial content and muscle mass. Eight-week-old male Institute of Cancer Research (ICR) mice underwent unilateral sciatic nerve transection surgery. The contralateral hindlimb served as a sham-operated control. From the day of surgery, mice were injected intraperitoneally with phosphate-buffered saline (PBS) or sodium lactate (equivalent to 1 g/kg body weight) once daily for 9 days. After 10 days of denervation, gastrocnemius muscle weight decreased to a similar extent in both the PBS- and lactate-injected groups. Denervation significantly decreased mitochondrial enzyme activity, protein content, and MCT4 protein content in the gastrocnemius muscle. However, lactate administration did not have any significant effects. The current observations suggest that daily lactate administration for 9 days does not affect denervation-induced loss of mitochondrial content and muscle mass.

Keywords: denervation; lactate; mitochondria; skeletal muscle

DOI: https://doi.org/10.1002/2211-5463.13293

Nat Rev Mol Cell Biol. 2021 Sep 13.

Molecular mechanisms of dietary restriction promoting health and longevity.

Cara L Green, Dudley W Lamming, Luigi Fontana.

Dietary restriction with adequate nutrition is the gold standard for delaying ageing and extending healthspan and lifespan in diverse species, including rodents and non-human primates. In this Review, we discuss the effects of dietary restriction in these mammalian model organisms and discuss accumulating data that suggest that dietary restriction results in many of the same physiological, metabolic and molecular changes responsible for the prevention of multiple ageing-associated diseases in humans. We further discuss how different forms of fasting, protein restriction and specific reductions in the levels of essential amino acids such as methionine and the branched-chain amino acids selectively impact the activity of AKT, FOXO, mTOR, nicotinamide adenine dinucleotide (NAD+), AMP-activated protein kinase (AMPK) and fibroblast growth factor 21 (FGF21), which are key components of some of the most important nutrient-sensing geroprotective signalling pathways that promote healthy longevity.

DOI: https://doi.org/10.1038/s41580-021-00411-4