bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2021‒04‒11
three papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. EMBO Rep. 2021 Apr 06. e51532
      Ferroptosis has recently attracted much interest because of its relevance to human diseases such as cancer and ischemia-reperfusion injury. We have reported that prolonged severe cold stress induces lipid peroxidation-dependent ferroptosis, but the upstream mechanism remains unknown. Here, using genome-wide CRISPR screening, we found that a mitochondrial Ca2+ uptake regulator, mitochondrial calcium uptake 1 (MICU1), is required for generating lipid peroxide and subsequent ferroptosis under cold stress. Furthermore, the gatekeeping activity of MICU1 through mitochondrial calcium uniporter (MCU) is suggested to be indispensable for cold stress-induced ferroptosis. MICU1 is required for mitochondrial Ca2+ increase, hyperpolarization of the mitochondrial membrane potential (MMP), and subsequent lipid peroxidation under cold stress. Collectively, these findings suggest that the MICU1-dependent mitochondrial Ca2+ homeostasis-MMP hyperpolarization axis is involved in cold stress-induced lipid peroxidation and ferroptosis.
    Keywords:  CRISPR screening; Ca2+; MICU1; cold stress-induced ferroptosis; mitochondria
  2. FEBS Lett. 2021 Apr 10.
      Mitochondria play a key role in cellular signalling, metabolism and energetics. Proper architecture and remodelling of the inner mitochondrial membrane are essential for efficient respiration, apoptosis and quality control in the cell. Several protein complexes including mitochondrial contact site and cristae organising system (MICOS), F1 FO -ATP synthase, and Optic Atrophy 1 (OPA1), facilitate formation, maintenance and stability of cristae membranes. MICOS, the F1 FO -ATP synthase, OPA1 and inner membrane phospholipids such as cardiolipin and phosphatidylethanolamine interact with each other to organise the inner membrane ultra-structure and remodel cristae in response to the cell's demands. Functional alterations in these proteins or in the biosynthesis pathway of cardiolipin and phosphatidylethanolamine result in an aberrant inner membrane architecture and impair mitochondrial function. Mitochondrial dysfunction and abnormalities hallmark several human conditions and diseases including neurodegeneration, cardiomyopathies and diabetes mellitus. Yet, they have long been regarded as secondary pathological effects. This review discusses emerging evidence of a direct relationship between protein- and lipid-dependent regulation of the inner mitochondrial membrane morphology and diseases such as fatal encephalopathy, Leigh syndrome, Parkinson's disease, and cancer.
    Keywords:  ATP synthase; MICOS; Mitochondria; Opa1; membrane dynamics; membrane morphology; mitochondrial morphology; mitochondrial ultra-structure
  3. Sci Transl Med. 2021 Apr 07. pii: eabb0319. [Epub ahead of print]13(588):
      Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy, and despite advances in genetic and pharmacological disease-modifying treatments, its management remains a major challenge. Mitochondrial dysfunction contributes to DMD, yet the mechanisms by which this occurs remain elusive. Our data in experimental models and patients with DMD show that reduced expression of genes involved in mitochondrial autophagy, or mitophagy, contributes to mitochondrial dysfunction. Mitophagy markers were reduced in skeletal muscle and in muscle stem cells (MuSCs) of a mouse model of DMD. Administration of the mitophagy activator urolithin A (UA) rescued mitophagy in DMD worms and mice and in primary myoblasts from patients with DMD, increased skeletal muscle respiratory capacity, and improved MuSCs' regenerative ability, resulting in the recovery of muscle function and increased survival in DMD mouse models. These data indicate that restoration of mitophagy alleviates symptoms of DMD and suggest that UA may have potential therapeutic applications for muscular dystrophies.