bims-mireme Biomed News
on Mitochondria in regenerative medicine
Issue of 2021‒04‒18
six papers selected by
Brian Spurlock
University of Alabama at Birmingham

  1. Adv Sci (Weinh). 2021 Apr;8(7): 2003516
      Cell reprogramming is considered a stochastic process, and it is not clear which cells are prone to be reprogrammed and whether a deterministic step exists. Here, asymmetric cell division (ACD) at the early stage of induced neuronal (iN) reprogramming is shown to play a deterministic role in generating elite cells for reprogramming. Within one day, fibroblasts underwent ACD, with one daughter cell being converted into an iN precursor and the other one remaining as a fibroblast. Inhibition of ACD significantly inhibited iN conversion. Moreover, the daughter cells showed asymmetric DNA segregation and histone marks during cytokinesis, and the cells inheriting newly replicated DNA strands during ACD became iN precursors. These results unravel a deterministic step at the early phase of cell reprogramming and demonstrate a novel role of ACD in cell phenotype change. This work also supports a novel hypothesis that daughter cells with newly replicated DNA strands are elite cells for reprogramming, which remains to be tested in various reprogramming processes.
    Keywords:  asymmetric cell division; cell fate determination; direct reprogramming; epigenetic state
  2. Stem Cell Reports. 2021 Apr 03. pii: S2213-6711(21)00152-1. [Epub ahead of print]
      Mitochondrial state changes were shown to be critical for stem cell function. However, variation in the mitochondrial content in stem cells and the implication, if any, on differentiation is poorly understood. Here, using cellular and molecular studies, we show that the planarian pluripotent stem cells (PSCs) have low mitochondrial mass compared with their progenitors. Transplantation experiments provided functional validation that neoblasts with low mitochondrial mass are the true PSCs. Further, the mitochondrial mass correlated with OxPhos and inhibiting the transition to OxPhos dependent metabolism in cultured cells resulted in higher PSCs. In summary, we show that low mitochondrial mass is a hallmark of PSCs in planaria and provide a mechanism to isolate live, functionally active, PSCs from different cell cycle stages (G0/G1 and S, G2/M). Our study demonstrates that the change in mitochondrial metabolism, a feature of PSCs is conserved in planaria and highlights its role in organismal regeneration.
    Keywords:  FACS; differentiation; mitochondria; neoblasts; planaria; pluripotency; stem cells
  3. Biosystems. 2021 Apr 12. pii: S0303-2647(21)00081-2. [Epub ahead of print] 104426
      Mitochondria's significance in human diseases and in functioning, health and death of eukaryotic cell has been acknowledged widely. Yet our perspective in cell biology and evolution remains nucleocentric. Mitochondrial DNA, by virtue of its omnipresence and species-level conservation, is used as a barcode in animal taxonomy. This article analyses various levels of containment structures that enclose mitochondrial DNA and advocates a fresh perspective wherein evolution of organic structures of the eukarya domain seem to support and facilitate survival and proliferation of mitochondrial DNA by splitting containers as they age and by directing them along two distinct pathways: destruction of containers with more mutant mitochondrial DNA and rejuvenation of containers with less mutant mitochondrial DNA.
    Keywords:  Eukaryotes; Eukaryotic cell; Evolution; Mitochondria; Mitochondrial DNA
  4. Biochem J. 2021 Apr 12. pii: BCJ20200975. [Epub ahead of print]
      Inorganic polyphosphate (polyP) is a linear polymer composed of up to a few hundred orthophosphates linked together by high-energy phosphoanhydride bonds, identical to those found in ATP. In mammalian mitochondria, polyP has been implicated in multiple processes, including energy metabolism, ion channels function, and the regulation of calcium signaling. However, the specific mechanisms of all these effects of polyP within the organelle remain poorly understood. The central goal of this study was to investigate how mitochondrial polyP participates in the regulation of the mammalian cellular energy metabolism. To accomplish this, we created HEK293 cells depleted of mitochondrial polyP, through the stable expression of the polyP hydrolyzing enzyme (scPPX). We found that these cells have significantly reduced rates of oxidative phosphorylation (OXPHOS), while their rates of glycolysis were elevated. Consistent with this, metabolomics assays confirmed increased levels of metabolites involved in glycolysis in these cells, compared with the wild-type samples. At the same time, key respiratory parameters of the isolated mitochondria were unchanged, suggesting that respiratory chain activity is not affected by the lack of mitochondrial polyP. However, we detected that mitochondria from cells that lack mitochondrial polyP are more fragmented when compared with those from wild-type cells. Based on these results, we propose that mitochondrial polyP plays an important role as a regulator of the metabolic switch between OXPHOS and glycolysis.
    Keywords:  glycolysis; inorganic polyphosphates; mitochondrial bioenergetics; oxidative phosphorylation; polyP
  5. Bone. 2021 Apr 01. pii: S8756-3282(21)00103-4. [Epub ahead of print]148 115941
      Mitochondria are essential organelles that form highly complex, interconnected dynamic networks inside cells. The GTPase mitofusin 2 (MFN2) is a highly conserved outer mitochondrial membrane protein involved in the regulation of mitochondrial morphology, which can affect various metabolic and signaling functions. The role of mitochondria in bone formation remains unclear. Since MFN2 levels increase during osteoblast (OB) differentiation, we investigated the role of MFN2 in the osteolineage by crossing mice bearing floxed Mfn2 alleles with those bearing Prx-cre to generate cohorts of conditional knock out (cKO) animals. By ex vivo microCT, cKO female mice, but not males, display an increase in cortical thickness at 8, 18, and 30 weeks, compared to wild-type (WT) littermate controls. However, the cortical anabolic response to mechanical loading was not different between genotypes. To address how Mfn2 deficiency affects OB differentiation, bone marrow-derived mesenchymal stromal cells (MSCs) from both wild-type and cKO mice were cultured in osteogenic media with different levels of β-glycerophosphate. cKO MSCs show increased mineralization and expression of multiple markers of OB differentiation only at the lower dose. Interestingly, despite showing the expected mitochondrial rounding and fragmentation due to loss of MFN2, cKO MSCs have an increase in oxygen consumption during the first 7 days of OB differentiation. Thus, in the early phases of osteogenesis, MFN2 restrains oxygen consumption thereby limiting differentiation and cortical bone accrual during homeostasis in vivo.
    Keywords:  Bone formation; Mitochondria; Mitofusin; Osteoblast; Osteogenesis
  6. Geroscience. 2021 Apr 17.
      Mitochondria are organelles that provide energy to cells through ATP production. Mitochondrial dysfunction has long been postulated to mediate cellular declines that drive biological aging. Many well-characterized hallmarks of aging may involve underlying energetic defects that stem from loss of mitochondrial function with age. Why and how mitochondrial function declines with age is an open question and one that has been difficult to answer. Mitochondria are powered by an electrochemical gradient across the inner mitochondrial membrane known as the protonmotive force (PMF). This gradient decreases with age in several experimental models. However, it is unclear if a diminished PMF is a cause or a consequence of aging. Herein, we briefly review and define mitochondrial function, we summarize how PMF changes with age in several models, and we highlight recent studies that implicate PMF in aging biology. We also identify barriers that must be addressed for the field to progress. Emerging technology permits more precise in vivo study of mitochondria that will allow better understanding of cause and effect in metabolic models of aging. Once cause and effect can be discerned more precisely, energetics approaches to combat aging may be developed to prevent or reverse functional decline.
    Keywords:  AMPK; Autophagy; Membrane potential; Metabolism; mTOR