bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒10‒11
seven papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. Trends Cell Biol. 2020 Oct 06. pii: S0962-8924(20)30171-9. [Epub ahead of print]
      Sustaining both proteome and genome integrity (GI) requires the integration of a wide range of mechanisms and signaling pathways. These comprise, in particular, the unfolded protein response (UPR) and the DNA damage response (DDR). These adaptive mechanisms take place respectively in the endoplasmic reticulum (ER) and in the nucleus. UPR and DDR alterations are associated with aging and with pathologies such as degenerative diseases, metabolic and inflammatory disorders, and cancer. We discuss the emerging signaling crosstalk between UPR stress sensors and the DDR, as well as their involvement in cancer biology.
    Keywords:  ATM; DNA damage response; IRE1α; PERK; proteostasis; unfolded protein response
  2. Aging (Albany NY). 2020 Oct 06. 12
      The contribution of dysregulated mitochondrial gene expression and consequent imbalance in biogenesis is not well understood in metabolic disorders such as insulin resistance and obesity. The ribosomal RNA maturation protein PTCD1 is essential for mitochondrial protein synthesis and its reduction causes adult-onset obesity and liver steatosis. We used haploinsufficient Ptcd1 mice fed normal or high fat diets to understand how changes in mitochondrial biogenesis can lead to metabolic dysfunction. We show that Akt-stimulated reduction in lipid content and upregulation of mitochondrial biogenesis effectively protected mice with reduced mitochondrial protein synthesis from excessive weight gain on a high fat diet, resulting in improved glucose and insulin tolerance and reduced lipid accumulation in the liver. However, inflammation of the white adipose tissue and early signs of fibrosis in skeletal muscle, as a consequence of reduced protein synthesis, were exacerbated with the high fat diet. We identify that reduced mitochondrial protein synthesis and OXPHOS biogenesis can be recovered in a tissue-specific manner via Akt-mediated increase in insulin sensitivity and transcriptional activation of the mitochondrial stress response.
    Keywords:  mTOR and insulin signaling pathways; metabolic syndrome; mitochondria; obesity; stress response
  3. Cell Metab. 2020 Oct 06. pii: S1550-4131(20)30486-1. [Epub ahead of print]
      Alterations in muscle mitochondrial substrate preference have been postulated to play a major role in the pathogenesis of muscle insulin resistance. In order to examine this hypothesis, we assessed the ratio of mitochondrial pyruvate oxidation (VPDH) to rates of mitochondrial citrate synthase flux (VCS) in muscle. Contrary to this hypothesis, we found that high-fat-diet (HFD)-fed insulin-resistant rats did not manifest altered muscle substrate preference (VPDH/VCS) in soleus or quadriceps muscles in the fasting state. Furthermore, hyperinsulinemic-euglycemic (HE) clamps increased VPDH/VCS in both muscles in normal and insulin-resistant rats. We then examined the muscle VPDH/VCS flux in insulin-sensitive and insulin-resistant humans and found similar relative rates of VPDH/VCS, following an overnight fast (∼20%), and similar increases in VPDH/VCS fluxes during a HE clamp. Altogether, these findings demonstrate that alterations in mitochondrial substrate preference are not an essential step in the pathogenesis of muscle insulin resistance.
    Keywords:  Randle Cycle; citrate synthase; glucose oxidation; insulin resistance; metabolic flux; metabolic inflexibility; mitochondria; muscle metabolism; pyruvate dehydrogenase; respiratory quotient
  4. Cell Metab. 2020 Oct 06. pii: S1550-4131(20)30492-7. [Epub ahead of print]32(4): 512-513
      Mitochondrial dysfunction is a hallmark of heart disease. Nicolás-Ávila et al. (2020) now find that cardiomyocytes eject dysfunctional mitochondria in exopher vesicles, which require elimination by specialized heart-resident macrophages, altogether supporting proper heart function.
  5. Cell Rep. 2020 Oct 06. pii: S2211-1247(20)31220-1. [Epub ahead of print]33(1): 108231
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive fibrosis and hypovascularization, resulting in significant intratumoral hypoxia (low oxygen) that contributes to its aggressiveness, therapeutic resistance, and high mortality. Despite oxygen being a fundamental requirement for many cellular and metabolic processes, and the severity of hypoxia in PDAC, the impact of oxygen deprivation on PDAC biology is poorly understood. Investigating how PDAC cells survive in the near absence of oxygen, we find that PDAC cell lines grow robustly in oxygen tensions down to 0.1%, maintaining mitochondrial morphology, membrane potential, and the oxidative metabolic activity required for the synthesis of key metabolites for proliferation. Disrupting electron transfer efficiency by targeting mitochondrial respiratory supercomplex assembly specifically affects hypoxic PDAC proliferation, metabolism, and in vivo tumor growth. Collectively, our results identify a mechanism that enables PDAC cells to thrive in severe, oxygen-limited microenvironments.
    Keywords:  COX7A2L; aspartate; electron transport chain; hypoxia; pancreatic cancer; respiration; supercomplexes
  6. Cell. 2020 Sep 24. pii: S0092-8674(20)31091-6. [Epub ahead of print]
      Mg2+ is the most abundant divalent cation in metazoans and an essential cofactor for ATP, nucleic acids, and countless metabolic enzymes. To understand how the spatio-temporal dynamics of intracellular Mg2+ (iMg2+) are integrated into cellular signaling, we implemented a comprehensive screen to discover regulators of iMg2+ dynamics. Lactate emerged as an activator of rapid release of Mg2+ from endoplasmic reticulum (ER) stores, which facilitates mitochondrial Mg2+ (mMg2+) uptake in multiple cell types. We demonstrate that this process is remarkably temperature sensitive and mediated through intracellular but not extracellular signals. The ER-mitochondrial Mg2+ dynamics is selectively stimulated by L-lactate. Further, we show that lactate-mediated mMg2+ entry is facilitated by Mrs2, and point mutations in the intermembrane space loop limits mMg2+ uptake. Intriguingly, suppression of mMg2+ surge alleviates inflammation-induced multi-organ failure. Together, these findings reveal that lactate mobilizes iMg2+ and links the mMg2+ transport machinery with major metabolic feedback circuits and mitochondrial bioenergetics.
    Keywords:  Mrs2; calcium; cancer; channel; endoplasmic reticulum; inflammation; lactate; magnesium; metabolism; mitochondria
  7. EMBO Rep. 2020 Oct 05. e51015
      Respiratory chains are crucial for cellular energy conversion and consist of multi-subunit complexes that can assemble into supercomplexes. These structures have been intensively characterized in various organisms, but their physiological roles remain unclear. Here, we elucidate their function by leveraging a high-resolution structural model of yeast respiratory supercomplexes that allowed us to inhibit supercomplex formation by mutation of key residues in the interaction interface. Analyses of a mutant defective in supercomplex formation, which still contains fully functional individual complexes, show that the lack of supercomplex assembly delays the diffusion of cytochrome c between the separated complexes, thus reducing electron transfer efficiency. Consequently, competitive cellular fitness is severely reduced in the absence of supercomplex formation and can be restored by overexpression of cytochrome c. In sum, our results establish how respiratory supercomplexes increase the efficiency of cellular energy conversion, thereby providing an evolutionary advantage for aerobic organisms.
    Keywords:  bioenergetics; competitive fitness; cryo-EM; mitochondria; respiratory chain supercomplexes