mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases

Kidney Int. 2019 Feb;95(2):455-466. doi: 10.1016/j.kint.2018.08.038. Epub 2018 Nov 22.

Abstract

Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR). The human mitochondrial disorder MELAS/MIDD (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes/Maternally Inherited Diabetes and Deafness) shares many phenotypic characteristics with Leigh syndrome. MELAS/MIDD often leads to organ failure and transplantation and there are currently no effective treatments. To examine the therapeutic potential of mTOR inhibition in human mitochondrial disease, four kidney transplant recipients with MELAS/MIDD were switched from calcineurin inhibitors to mTOR inhibitors for immunosuppression. Primary fibroblast lines were generated from patient dermal biopsies and the impact of rapamycin was studied using cell-based end points. Metabolomic profiles of the four patients were obtained before and after the switch. pS6, a measure of mTOR signaling, was significantly increased in MELAS/MIDD cells compared to controls in the absence of treatment, demonstrating mTOR overactivation. Rapamycin rescued multiple deficits in cultured cells including mitochondrial morphology, mitochondrial membrane potential, and replicative capacity. Clinical measures of health and mitochondrial disease progression were improved in all four patients following the switch to an mTOR inhibitor. Metabolomic analysis was consistent with mitochondrial function improvement in all patients.

Keywords: chronic kidney disease; mitochondria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Allografts / cytology
  • Allografts / drug effects
  • Allografts / pathology
  • Animals
  • Calcineurin Inhibitors / pharmacology
  • Calcineurin Inhibitors / therapeutic use
  • Cells, Cultured
  • Deafness / complications
  • Deafness / pathology
  • Deafness / surgery*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / surgery*
  • Disease Progression
  • Female
  • Graft Rejection / immunology
  • Graft Rejection / pathology
  • Graft Rejection / prevention & control*
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Immunosuppressive Agents / therapeutic use
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / pathology
  • Kidney Failure, Chronic / etiology
  • Kidney Failure, Chronic / pathology
  • Kidney Failure, Chronic / surgery*
  • Kidney Transplantation / adverse effects*
  • MELAS Syndrome / complications
  • MELAS Syndrome / pathology
  • MELAS Syndrome / surgery*
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Middle Aged
  • Mitochondria / drug effects
  • Mitochondria / pathology
  • Mitochondrial Diseases / complications
  • Mitochondrial Diseases / pathology
  • Mitochondrial Diseases / surgery*
  • Primary Cell Culture
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / immunology
  • Treatment Outcome

Substances

  • Calcineurin Inhibitors
  • Immunosuppressive Agents
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Sirolimus

Supplementary concepts

  • Noninsulin-dependent diabetes mellitus with deafness