bims-misrem 2020-08-02 papers

Issue of 2020‒08‒02
five papers selected by
Rafael Antonio Casuso Pérez
University of Granada

Geroscience. 2020 Jul 31.

High-intensity exercise training induces mitonuclear imbalance and activates the mitochondrial unfolded protein response in the skeletal muscle of aged mice.

André Victor Cordeiro, Guilherme Francisco Peruca, Renata Rosseto Braga, Rafael Santos Brícola, Luciene Lenhare, Vagner Ramon Rodrigues Silva, Chadi Pellegrini Anaruma, Carlos Kiyoshi Katashima, Barbara Moreira Crisol, Lucas Torres Barbosa, Fernando Moreira Simabuco, Adelino Sanchez Ramos da Silva, Dennys Esper Cintra, Leandro Pereira de Moura, José Rodrigo Pauli, Eduardo Rochete Ropelle.

The impairment of mitochondrial metabolism is a hallmark of aging. Mitonuclear imbalance and the mitochondrial unfolded protein response (UPRmt) are two conserved mitochondrial mechanisms that play critical roles in ensuring mitochondrial proteostasis and function. Here, we combined bioinformatics, physiological, and molecular analyses to examine the role of mitonuclear imbalance and UPRmt in the skeletal muscle of aged rodents and humans. The analysis of transcripts from the skeletal muscle of aged humans (60-70 years old) revealed that individuals with higher levels of UPRmt-related genes displayed a consistent increase in several mitochondrial-related genes, including the OXPHOS-associated genes. Interestingly, high-intensity interval training (HIIT) was effective in stimulating the mitonuclear imbalance and UPRmt in the skeletal muscle of aged mice. Furthermore, these results were accompanied by higher levels of several mitochondrial markers and improvements in physiological parameters and physical performance. These data indicate that the maintenance or stimulation of the mitonuclear imbalance and UPRmt in the skeletal muscle could ensure mitochondrial proteostasis during aging, revealing new insights into targeting mitochondrial metabolism by using physical exercise.

Keywords: Aging; Exercise; Mitonuclear imbalance; Skeletal muscle; UPRmt

DOI: https://doi.org/10.1007/s11357-020-00246-5

Int J Mol Sci. 2020 Jul 23. pii: E5236. [Epub ahead of print]21(15):

Evelyn Ferri, Emanuele Marzetti, Riccardo Calvani, Anna Picca, Matteo Cesari, Beatrice Arosio.

Skeletal muscle aging is associated with a significant loss of skeletal muscle strength and power (i.e., dynapenia), muscle mass and quality of life, a phenomenon known as sarcopenia. This condition affects nearly one-third of the older population and is one of the main factors leading to negative health outcomes in geriatric patients. Notwithstanding the exact mechanisms responsible for sarcopenia are not fully understood, mitochondria have emerged as one of the central regulators of sarcopenia. In fact, there is a wide consensus on the assumption that the loss of mitochondrial integrity in myocytes is the main factor leading to muscle degeneration. Mitochondria are also key players in senescence. It has been largely proven that the modulation of mitochondrial functions can induce the death of senescent cells and that removal of senescent cells improves musculoskeletal health, quality, and function. In this review, the crosstalk among mitochondria, cellular senescence, and sarcopenia will be discussed with the aim to elucidate the role that the musculoskeletal cellular senescence may play in the onset of sarcopenia through the mediation of mitochondria.

Keywords: mitochondria; mitochondrial dysfunction; muscle aging; sarcopenia; skeletal muscle

DOI: https://doi.org/10.3390/ijms21155236

Ageing Res Rev. 2020 Jul 22. pii: S1568-1637(20)30264-6. [Epub ahead of print] 101129

Mitophagy Receptors and Mediators: Therapeutic Targets in the Management of Cardiovascular Ageing.

Amir Ajoolabady, Hamid Aslkhodapasandhokmabad, Ayuob Aghanejad, Yingmei Zhang, Jun Ren.

Mitophagy serves as a cardinal regulator in the maintenance of mitochondrial integrity, function, and cardiovascular homeostasis, through the fine control and governance of cellular metabolism, ATP production, redox balance, and mitochondrial quality and quantity control. As a unique form of selective autophagy, mitophagy specifically recognizes and engulfs long-lived or damaged (depolarized) mitochondria through formation of the double-membraned intracellular organelles - mitophagosomes, ultimately resulting in lysosomal degradation. Levels of mitophagy are reported to be altered in pathological settings including cardiovascular diseases and biological ageing although the precise nature of mitophagy change in ageing and ageing-associated cardiovascular deterioration remains poorly defined. Ample clinical and experimental evidence has depicted a convincing tie between cardiovascular ageing and altered mitophagy. In particular, ageing perturbs multiple enigmatic various signal machineries governing mitophagy, mitochondrial quality, and mitochondrial function, contributing to ageing-elicited anomalies in the cardiovascular system. This review will update novel regulatory mechanisms of mitophagy especially in the perspective of advanced ageing, and discuss how mitophagy dysregulation may be linked to cardiovascular abnormalities in ageing. We hope to pave the way for development of new therapeutic strategies against the growing health and socieconomical issue of cardiovascular ageing through targeting mitophagy.

Keywords: Ageing; Cardiovascular Diseases; Mitochondria; Mitophagy

DOI: https://doi.org/10.1016/j.arr.2020.101129

J Physiol. 2020 Jul 31.

In vitro ketone-supported mitochondrial respiration is minimal when other substrates are readily available in cardiac and skeletal muscle.

Heather L Petrick, Henver S Brunetta, Chris Pignanelli, Everson A Nunes, Luc J C van Loon, Jamie F Burr, Graham P Holloway.

KEY POINTS: Ketone bodies are proposed to represent an alternative fuel source driving energy production, particularly during exercise. Biologically, the extent to which mitochondria utilize ketone bodies compared to other substrates remains unknown. We demonstrate in vitro that maximal mitochondrial respiration supported by ketone bodies is low when compared to carbohydrate-derived substrates in the left ventricle and red gastrocnemius muscle from rodents, and in human skeletal muscle. When considering intramuscular concentrations of ketone bodies and the presence of other carbohydrate and lipid substrates, biological rates of mitochondrial respiration supported by ketone bodies are predicted to be minimal. At the mitochondrial level, it is therefore unlikely that ketone bodies are an important source for energy production in cardiac and skeletal muscle, particularly when other substrates are readily available.ABSTRACT: Ketone bodies (KB) have recently gained popularity as an alternative fuel source to support mitochondrial oxidative phosphorylation and enhance exercise performance. However, given the low activity of ketolytic enzymes and potential inhibition from carbohydrate oxidation, it remains unknown if KBs can contribute to energy production. We therefore determined the ability of KBs (sodium DL-β-hydroxybutyrate, β-HB; lithium acetoacetate, AcAc) to stimulate in vitro mitochondrial respiration in the left ventricle (LV) and red gastrocnemius (RG) of rats, and in human vastus lateralis. Compared to pyruvate, the ability of KBs to maximally drive respiration was low in isolated mitochondria and permeabilized fibres (PmFb) from the LV (∼30-35% of pyruvate), RG (∼10-30%), and human vastus lateralis (∼2-10%). In PmFb, the concentration of KBs required to half-maximally drive respiration (LV: 889 μm β-HB, 801 μm AcAc; RG: 782 μm β-HB, 267 μm AcAc) were greater than KB content representative of the muscle microenvironment (∼100 μm). This would predict low rates (∼1-4% of pyruvate) of biological KB-supported respiration in the LV (8-14 pmol·sec-1 ·mg-1 ) and RG (3-6 pmol·sec-1 ·mg-1 ) at rest and following exercise. Moreover, KBs did not increase respiration in the presence of saturating pyruvate, submaximal pyruvate (100 μm) reduced the ability of physiological β-HB to drive respiration, and addition of other intracellular substrates (succinate, palmitoylcarnitine) decreased maximal KB-supported respiration. As a result, product inhibition likely limits KB oxidation. Altogether, the ability of KBs to drive mitochondrial respiration is minimal and they are likely outcompeted by other substrates, compromising their use as an important energy source. This article is protected by copyright. All rights reserved.

Keywords: bioenergetics; ketone bodies; metabolism; mitochondria

DOI: https://doi.org/10.1113/JP280032

Nature. 2020 Jul 29.

Na+ controls hypoxic signalling by the mitochondrial respiratory chain.

All metazoans depend on the consumption of O2 by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O2 to produce reactive oxygen species that can drive cell adaptations1-4, a phenomenon that occurs in hypoxia4-8 and whose precise mechanism remains unknown. Ca2+ is the best known ion that acts as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential10. Here we show that Na+ acts as a second messenger that regulates OXPHOS function and the production of reactive oxygen species by modulating the fluidity of the inner mitochondrial membrane. A conformational shift in mitochondrial complex I during acute hypoxia11 drives acidification of the matrix and the release of free Ca2+ from calcium phosphate (CaP) precipitates. The concomitant activation of the mitochondrial Na+/Ca2+ exchanger promotes the import of Na+ into the matrix. Na+ interacts with phospholipids, reducing inner mitochondrial membrane fluidity and the mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III. The inhibition of Na+ import through the Na+/Ca2+ exchanger is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences for cellular metabolism.

DOI: https://doi.org/10.1038/s41586-020-2551-y