Cell Metabolic Alterations due to Mcph1 Mutation in Microcephaly

Cell Rep. 2020 Apr 14;31(2):107506. doi: 10.1016/j.celrep.2020.03.070.


A distinctive feature of neocortical development is the highly coordinated production of different progenitor cell subtypes, which are critical for ensuring adequate neurogenic outcome and the development of normal neocortical size. To further understand the mechanisms that underlie neocortical growth, we focused our studies on the microcephaly gene Mcph1, and we report here that Mcph1 (1) exerts its functions in rapidly dividing apical radial glial cells (aRGCs) during mouse neocortical development stages that precede indirect neurogenesis; (2) is expressed at mitochondria; and (3) controls the proper proliferation and survival of RGCs, potentially through crosstalk with cellular metabolic pathways involving the stimulation of mitochondrial activity via VDAC1/GRP75 and AKT/HK2/VDAC1 and glutaminolysis via ATF4/PCK2. We currently report the description of a MCPH-gene implication in the interplay between bioenergetic pathways and neocortical growth, thus pointing to alterations of cellular metabolic pathways, in particular glutaminolysis, as a possible cause of microcephalic pathogenesis.

Keywords: ATF4; GRP75; PCK2; VDAC1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation / genetics
  • Cell Proliferation / genetics
  • Cell Survival / genetics
  • Cytoskeletal Proteins / genetics*
  • Cytoskeletal Proteins / metabolism
  • Female
  • HEK293 Cells
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microcephaly / genetics*
  • Microcephaly / metabolism*
  • Microcephaly / physiopathology
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Mutation
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis / genetics
  • Neuroglia / metabolism
  • Neurons / metabolism
  • Voltage-Dependent Anion Channel 1 / genetics
  • Voltage-Dependent Anion Channel 1 / metabolism


  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • HSP70 Heat-Shock Proteins
  • HSPA9 protein, human
  • MCPH1 protein, human
  • Mitochondrial Proteins
  • Nerve Tissue Proteins
  • VDAC1 protein, human
  • Voltage-Dependent Anion Channel 1