Research Paper Volume 12, Issue 19 pp 19677—19700

Reduced mitochondrial translation prevents diet-induced metabolic dysfunction but not inflammation

Kara L. Perks1,2, , Nicola Ferreira1, , Judith A. Ermer1, , Danielle L. Rudler1, , Tara R. Richman1, , Giulia Rossetti1, , Vance B. Matthews3, , Natalie C. Ward4,5, , Oliver Rackham1,2,6, , Aleksandra Filipovska1,7, ,

  • 1 Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, University of Western Australia, Nedlands, Western Australia, Australia
  • 2 School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Western Australia, Australia
  • 3 School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia
  • 4 Medical School, Royal Perth Hospital Unit, University of Western Australia, Perth, Western Australia, Australia
  • 5 School of Public Health and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
  • 6 Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia
  • 7 School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia, Australia

Received: July 14, 2020       Accepted: July 21, 2020       Published: October 6, 2020
How to Cite

Copyright: © 2020 Perks et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


Akt: protein kinase B; CHOP: CCAAT-enhancer-binding protein homologous protein; HFD: high fat diet; mTOR: mammalian target of rapamycin; NCD: normal chow diet; OXPHOS: oxidative phosphorylation; OCR: oxygen consumption rate; PTCD1: pentatricopeptide repeat domain protein 1; SCFA: short chain fatty acid; WAT: white adipose tissue.