Oral Presentation 4th Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity Meeting 2024

Early mitochondrial dysfunction aligns with risk for kidney disease in diabetes (#35)

Mitchell A Sullivan 1 2 , Amelia K Fotheringham 1 3 , Uyen N Pham 1 3 4 , Domenica A McCarthy 1 , Herma Renkema 5 , Jan Smeitink 5 , David R Thorburn 6 7 , Kristof Boot 1 , Preeti Chandrashekar 1 3 , Rani O Whiddett 1 , Nicole Flemming 1 2 3 , Irina Buckle 1 , Kim M Summers 1 , Mark P Hodson 8 9 , Neisha De Silva 4 , Janelle Nisbet 4 , Adam Morton 4 , Stephanie Teasdale 4 , David P De Souza 10 , Sheik N D Doomun 10 , Nicole Isbel 3 11 , Elizabeth A Davis 12 13 , Timothy W Jones 12 13 , Mark Harris 14 , Jennifer Couper 15 , Melinda T Coughlan 16 17 , David W Johnson 3 11 , Maria E Craig 18 , Alison Pryke 18 , Andrew M Cotterill 14 , Paul Benitez 18 , M Loredana Marcovecchio 19 , Trisha O'Moore-Sullivan 3 4 , Helen L Barrett 1 4 20 , Kim C Donaghue 18 , Josephine M Forbes 1 3 4 6
  1. Mater Research Institute - The University of Queensland, Brisbane, QLD, Australia
  2. School of Health, The University of the Sunshine Coast, Sippy Downs, Qld, Australia
  3. Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
  4. Mater Young Adults Health Centre, Mater Misericordiae Ltd, Brisbane, QLD, Australia
  5. Khondrion BV, Nijmegan, Gelderland , The Netherlands
  6. Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
  7. Murdoch Children's Research Institute, Parkville, VIC, Australia
  8. QIMR Berghofer MRI, Brisbane, Qld, Australia
  9. School of Pharmacy, The University of Queensland, Brisbane, Qld, Australia
  10. Metabolomics Australia, The University of Melbourne, Melbourne, VIC, Australia
  11. Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Qld, Australia
  12. Telethon Kid's Institute, Perth, WA, Australia
  13. Department of Diabetes and Endocrinology, Perth Children's Hospital, Nedlands, WA, Australia
  14. Department of Endocrinology and Diabetes, Queensland Children’s Hospital, Brisbane, Qld, Australia
  15. Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
  16. Department of Diabetes, Monash University, Melbourne, VIC, Australia
  17. Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
  18. Children’s Hospital at Westmead , The University of Sydney, Sydney, NSW, Australia
  19. Department of Paediatrics, University of Cambridge , Cambridge, Cambridgeshire, UK
  20. School of Women’s and Child’s Health Medicine, University of NSW, Sydney, NSW, Australia

Globally, the prevalence of diabetic kidney disease (DKD) continues to rise at an alarming rate and is a major risk factor for premature death. Early age at diabetes diagnosis exacerbates the risk for DKD, with most adult therapies having fewer benefits in youth, but there is a lag in the molecular understanding of this in humans. Here we show that mitochondrial dysfunction is present in youth with high DKD risk and that a mitochondrial therapy (MitoTx) targeting this pathway may be efficacious. Firstly, we demonstrate that mice with a heterozygous mutation in mitochondrial complex I subunit Ndufs6, common in humans (1:250), exhibit impairment in kidney function, as well as proximal tubule and kidney immune cell mitochondrial dysfunction, which are amplified by diabetes and reversed with MitoTx. MitoTx’s therapeutic benefit was confirmed in a second murine model of diabetes and early kidney disease. Secondly, we studied three cohorts of youth with diabetes and varied risk for DKD. In young adults (YA) with type 1 diabetes (T1DM; 20±3 yrs, n=100), recruited in Brisbane, Australia, stratified for future DKD risk (low, uACR<1.17, n=66 vs high, uACR≥1.17 mg/mmol, n=34), greater mitochondrial dysfunction in circulating CD4+T cells, particularly Treg was evident in high-risk individuals using functional ATP production assays, flow cytometry and fuel changes by plasma metabolomics. Human proximal tubule kidney cells exposed to high-risk patient plasma showed mitochondrial defects in both fatty acid β-oxidation and non-fatty acid-derived ATP production. As a predictive biomarker of mitochondrial dysfunction, urine mtDNA:nDNA was associated with greater urinary albumin excretion both in YA and in a second cohort of adolescents (n=80, 14±2 yrs). Finally, we also found a signature of mitochondrial dysfunction in biopsy kidney cells from youth onset diabetes and early DKD (n=6), using previously generated single-cell transcriptomics and gene availability data. Together, these studies postulate that mitochondrial dysfunction is an early and pathological manifestation in human DKD that can be therapeutically targeted and should be evaluated to prevent the onset and progression to overt kidney disease and premature death in people with diabetes.