A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance

Giulia Rossetti; Judith A Ermer; Maike Stentenbach; Stefan J Siira; Tara R Richman; Dusanka Milenkovic; Kara L Perks; Laetitia A Hughes; Emma Jamieson; Gulibaikelamu Xiafukaiti; Natalie C Ward; Satoru Takahashi; Nicola Gray; Helena M Viola; Livia C Hool; Oliver Rackham; Aleksandra Filipovska

doi:10.1126/sciadv.abi7514

A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance

Sci Adv. 2021 Sep 24;7(39):eabi7514. doi: 10.1126/sciadv.abi7514. Epub 2021 Sep 24.

Authors

Giulia Rossetti^{1

2

3}, Judith A Ermer^{1

2

3}, Maike Stentenbach^{1

2

3}, Stefan J Siira^{1

2

3}, Tara R Richman^{1

2

3}, Dusanka Milenkovic⁴, Kara L Perks^{1

2

3}, Laetitia A Hughes^{1

2

3}, Emma Jamieson⁵, Gulibaikelamu Xiafukaiti⁶, Natalie C Ward⁷, Satoru Takahashi⁶, Nicola Gray⁸, Helena M Viola⁹, Livia C Hool^{9

10}, Oliver Rackham^{1

2

11

12

13}, Aleksandra Filipovska^{1

2

3

13

14}

Affiliations

¹ Harry Perkins Institute of Medical Research, Nedlands, Western Australia 6009, Australia.
² ARC Centre of Excellence in Synthetic Biology, QEII Medical Centre, Nedlands, Western Australia 6009, Australia.
³ Centre for Medical Research, The University of Western Australia, QEII Medical Centre, Nedlands, Western Australia 6009, Australia.
⁴ Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany.
⁵ Faculty of Health and Medical Sciences, Medical School, The Rural Clinical School of Western Australia, The University of Western Australia, Bunbury, Western Australia 6230, Australia.
⁶ Department of Anatomy and Embryology, Faculty of Medicine, Laboratory Animal Resource Center (LARC), and Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
⁷ Dobney Hypertension Centre, Medical School, The University of Western Australia, Perth, Western Australia, Australia.
⁸ Australian National Phenome Centre, Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, Western Australia 6150, Australia.
⁹ School of Human Sciences (Physiology), The University of Western Australia, Crawley, Western Australia 6009, Australia.
¹⁰ Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, New South Wales 2010, Australia.
¹¹ Curtin Medical School, Curtin University, Bentley, Western Australia 6102, Australia.
¹² Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia 6102, Australia.
¹³ Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, 15 Hospital Avenue, Nedlands, Western Australia, Australia.
¹⁴ School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia 6009, Australia.

Abstract

Mitochondrial energy metabolism plays an important role in the pathophysiology of insulin resistance. Recently, a missense N437S variant was identified in the MRPP3 gene, which encodes a mitochondrial RNA processing enzyme within the RNase P complex, with predicted impact on metabolism. We used CRISPR-Cas9 genome editing to introduce this variant into the mouse Mrpp3 gene and show that the variant causes insulin resistance on a high-fat diet. The variant did not influence mitochondrial gene expression markedly, but instead, it reduced mitochondrial calcium that lowered insulin release from the pancreatic islet β cells of the Mrpp3 variant mice. Reduced insulin secretion resulted in lower insulin levels that contributed to imbalanced metabolism and liver steatosis in the Mrpp3 variant mice on a high-fat diet. Our findings reveal that the MRPP3 variant may be a predisposing factor to insulin resistance and metabolic disease in the human population.