bims-misrem 2021-07-25 papers

Issue of 2021‒07‒25
four papers selected by
Rafael Antonio Casuso Pérez
University of Granada

EMBO Rep. 2021 Jul 23. e51954

Mfn2 localization in the ER is necessary for its bioenergetic function and neuritic development.

Sergi Casellas-Díaz, Raquel Larramona-Arcas, Guillem Riqué-Pujol, Paula Tena-Morraja, Claudia Müller-Sánchez, Marc Segarra-Mondejar, Aleix Gavaldà-Navarro, Francesc Villarroya, Manuel Reina, Ofelia M Martínez-Estrada, Francesc X Soriano.

Mfn2 is a mitochondrial fusion protein with bioenergetic functions implicated in the pathophysiology of neuronal and metabolic disorders. Understanding the bioenergetic mechanism of Mfn2 may aid in designing therapeutic approaches for these disorders. Here we show using endoplasmic reticulum (ER) or mitochondria-targeted Mfn2 that Mfn2 stimulation of the mitochondrial metabolism requires its localization in the ER, which is independent of its fusion function. ER-located Mfn2 interacts with mitochondrial Mfn1/2 to tether the ER and mitochondria together, allowing Ca2+ transfer from the ER to mitochondria to enhance mitochondrial bioenergetics. The physiological relevance of these findings is shown during neurite outgrowth, when there is an increase in Mfn2-dependent ER-mitochondria contact that is necessary for correct neuronal arbor growth. Reduced neuritic growth in Mfn2 KO neurons is recovered by the expression of ER-targeted Mfn2 or an artificial ER-mitochondria tether, indicating that manipulation of ER-mitochondria contacts could be used to treat pathologic conditions involving Mfn2.

Keywords: Ca2+; ER-mitochondria tethering; Mfn2; neuritic growth

DOI: https://doi.org/10.15252/embr.202051954

Biochim Biophys Acta Mol Cell Res. 2021 Jul 15. pii: S0167-4889(21)00153-1. [Epub ahead of print] 119099

Keeping zombies alive: The ER-mitochondria Ca2+ transfer in cellular senescence.

Ulises Ahumada-Castro, Andrea Puebla-Huerta, Victor Cuevas-Espinoza, Alenka Lovy, J Cesar Cardenas.

Cellular senescence generates a permanent cell cycle arrest, characterized by apoptosis resistance and a pro-inflammatory senescence-associated secretory phenotype (SASP). Physiologically, senescent cells promote tissue remodeling during development and after injury. However, when accumulated over a certain threshold as happens during aging or after cellular stress, senescent cells contribute to the functional decline of tissues, participating in the generation of several diseases. Cellular senescence is accompanied by increased mitochondrial metabolism. How mitochondrial function is regulated and what role it plays in senescent cell homeostasis is poorly understood. Mitochondria are functionally and physically coupled to the endoplasmic reticulum (ER), the major calcium (Ca2+) storage organelle in mammalian cells, through special domains known as mitochondria-ER contacts (MERCs). In this domain, the release of Ca2+ from the ER is mainly regulated by inositol 1,4,5-trisphosphate receptors (IP3Rs), a family of three Ca2+ release channels activated by a ligand (IP3). IP3R-mediated Ca2+ release is transferred to mitochondria through the mitochondrial Ca2+ uniporter (MCU), where it modulates the activity of several enzymes and transporters impacting its bioenergetic and biosynthetic function. Here, we review the possible connection between ER to mitochondria Ca2+ transfer and senescence. Understanding the pathways that contribute to senescence is essential to reveal new therapeutic targets that allow either delaying senescent cell accumulation or reduce senescent cell burden to alleviate multiple diseases.

Keywords: MERCs; calcium; metabolism; mitochondria; senescence

DOI: https://doi.org/10.1016/j.bbamcr.2021.119099

Geroscience. 2021 Jul 20.

Eat like an athlete: insights of sports nutrition science to support active aging in healthy older adults.

Sara Y Oikawa, Tristin D Brisbois, Luc J C van Loon, Ian Rollo.

Skeletal muscle mass losses with age are associated with negative health consequences, including an increased risk of developing metabolic disease and the loss of independence. Athletes adopt numerous nutritional strategies to maximize the benefits of exercise training and enhance recovery in pursuit of improving skeletal muscle quality, mass, or function. Importantly, many of the principles applied to enhance skeletal muscle health in athletes may be applicable to support active aging and prevent sarcopenia in the healthy (non-clinical) aging population. Here, we discuss the anabolic properties of protein supplementation in addition to ingredients that may enhance the anabolic effects of protein (e.g. omega 3 s, creatine, inorganic nitrate) in older persons. We conclude that nutritional strategies used in pursuit of performance enhancement in athletes are often applicable to improve skeletal muscle health in the healthy older population when implemented as part of a healthy active lifestyle. Further research is required to elucidate the mechanisms by which these nutrients may induce favourable changes in skeletal muscle and to determine the appropriate dosing and timing of nutrient intakes to support active aging.

Keywords: Carbohydrate periodization; Creatine; Protein; Skeletal muscle; n-3PUFA

DOI: https://doi.org/10.1007/s11357-021-00419-w

Free Radic Biol Med. 2021 Jul 15. pii: S0891-5849(21)00419-6. [Epub ahead of print]173 1-6

Six weeks of high intensity cycle training reduces H2O2 emission and increases antioxidant protein levels in obese adults with risk factors for type 2 diabetes.

Mathias Flensted-Jensen, Martin Gram, Flemming Dela, Jørn Wulff Helge, Steen Larsen.

Obesity has been associated with increased production of reactive oxygen species (ROS), which may be involved in the development of cardiovascular disease and type 2 diabetes (T2D). Endurance exercise lowers ROS production and increases antioxidant capacity in muscle cells, but it is currently unknown whether high intensity interval training (HIT) elicits the same effects. Twelve sedentary obese subjects at risk of developing T2D took part in a six-week intervention, performing three HIT sessions per week (five 1-min sets of high-intensity cycling (125% of VO2peak), with 90 s recovery in between sets). Muscle biopsies were obtained for assessment of ROS production (H2O2 emission), mitochondrial respiratory capacity, and antioxidant protein levels before and after the intervention. H2O2 emission decreased 60.4% after the intervention (Succinate 3 mmol･l-1), concurrent with a 35.1% increase in protein levels of the antioxidant manganese superoxide dismutase (MnSOD) and a trend towards increased levels of the antioxidant catalase (p = 0.06, 72.9%). These findings were accompanied by a 19% increased mitochondrial respiratory capacity (CI + II), a 6.9% increased VO2peak and a 1.7% lower body fat percentage. These effects were achieved after just 15 min of high-intensity work and 40 min of total time spent per week. Overall, this suggests that a relatively small amount of HIT is sufficient to induce beneficial effects on ROS production and antioxidant status in muscle cells, which may lower oxidative stress and potentially protect against the development of cardiovascular disease.

Keywords: Antioxidants; HIT; Oxidative stress; Skeletal muscle

DOI: https://doi.org/10.1016/j.freeradbiomed.2021.07.020