3 results found
Lima A, Lubatti G, Burgstaller J, et al., 2021, Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development, Nature Metabolism, Vol: 3, Pages: 1091-1108, ISSN: 2522-5812
Cell competition is emerging as a quality control mechanism that eliminates unfit cells in a wide range of settings from development to the adult. However, the nature of the cells normally eliminated by cell competition and what triggers their elimination remains poorly understood. In mice, 35% of epiblast cells are eliminated prior to gastrulation. Here we show that cells with mitochondrial defects are eliminated by cell competition during early mouse development. Using single cell transcriptional profiling of eliminated mouse epiblast cells we identify hallmarks of cell competition and mitochondrial defects. We go on to demonstrate that mitochondrial defects are common to a range of different loser cell types and that manipulating mitochondrial function triggers cell competition. In the mouse embryo, cell competition eliminates cells with sequence changes in mt-Rnr1 and mt-Rnr2, and that even non-pathological changes in mitochondrial DNA sequence can induce cell competition. Our results suggest that cell competition is a purifying selection that optimises mitochondrial performance prior to gastrulation.
Lima A, Burgstaller J, Sanchez Nieto JM, et al., 2017, The mitochondria and the regulation of cell fitness during earlymammalian development, Current Topics in Developmental Biology, Vol: 128, Pages: 339-363, ISSN: 0070-2153
From fertilization until the onset of gastrulation the early mammalian embryo undergoes a dramatic series of changes that converts a single fertilized cell into a remarkably complex organism. Much attention has been given to the molecular changes occurring during this process, but here we will review what is known about the changes affecting the mitochondria and how they impact on the energy metabolism and apoptotic response of the embryo. We will also focus on understanding what quality control mechanisms ensure optimal mitochondrial activity in the embryo, and in this way provide an overview of the importance of the mitochondria in determining cell fitness during early mammalian development.
Willows R, Navaratnam N, Lima A, et al., 2017, Effect of different γ subunit isoforms on the regulation of AMPK, Biochemical Journal, Vol: 474, Pages: 1741-1754, ISSN: 1470-8728
AMP-activated protein kinase (AMPK) plays a key role in integrating metabolic pathways in response to energy demand. AMPK activation results in a wide range of downstream responses, many of which are associated with improved metabolic outcome, making AMPK an attractive target for the treatment of metabolic diseases. AMPK is a heterotrimeric complex consisting of a catalytic subunit (α) and two regulatory subunits (β and γ). The γ-subunit harbours the nucleotide-binding sites and plays an important role in AMPK regulation in response to cellular energy levels. In mammals, there are three isoforms of the γ-subunit and these respond differently to regulation by nucleotides, but there is limited information regarding their role in activation by small molecules. Here, we determined the effect of different γ-isoforms on AMPK by a direct activator, 991. In cells, 991 led to a greater activation of γ2-containing AMPK complexes compared with either γ1 or γ3. This effect was dependent on the long N-terminal region of the γ2-isoform. We were able to rule out an effect of Ser108 phosphorylation, since mutation of Ser108 to alanine in the β2-isoform had no effect on activation of AMPK by 991 in either γ1- or γ2-complexes. The rate of dephosphorylation of Thr172 was slower for γ2- compared with γ1-complexes, both in the absence and presence of 991. Our studies show that activation of AMPK by 991 depends on the nature of the γ-isoform. This finding may have implications for the design of isoform-selective AMPK activators.
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