mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases

Simon C. Johnson, Frank Martinez, Alessandro Bitto, Brenda Gonzalez, Cagdas Tazaerslan, Camille Cohen, Laure Delaval, José Timsit, Bertrand Knebelmann, Fabiola Terzi, Tarika Mahal, Yizhou Zhu, Philip G. Morgan, Margaret M. Sedensky, Matt Kaeberlein, Christophe Legendre, Yousin Suh, Guillaume Canaud

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
JournalKidney International
DOIs
StateAccepted/In press - Jan 1 2018

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Mitochondrial Diseases
Sirolimus
Kidney
Lactic Acidosis
Stroke
Leigh Disease
Metabolomics
Transplant Recipients
Mitochondrial Membrane Potential
Organ Transplantation
Therapeutics
Immunosuppression
Disease Progression
Cultured Cells
Fibroblasts
Pharmacology
Biopsy
Skin
Noninsulin-dependent diabetes mellitus with deafness
Mitochondrial encephalopathy

Keywords

  • chronic kidney disease
  • mitochondria

ASJC Scopus subject areas

  • Nephrology

Cite this

Johnson, S. C., Martinez, F., Bitto, A., Gonzalez, B., Tazaerslan, C., Cohen, C., ... Canaud, G. (Accepted/In press). mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases. Kidney International. https://doi.org/10.1016/j.kint.2018.08.038

mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases. / Johnson, Simon C.; Martinez, Frank; Bitto, Alessandro; Gonzalez, Brenda; Tazaerslan, Cagdas; Cohen, Camille; Delaval, Laure; Timsit, José; Knebelmann, Bertrand; Terzi, Fabiola; Mahal, Tarika; Zhu, Yizhou; Morgan, Philip G.; Sedensky, Margaret M.; Kaeberlein, Matt; Legendre, Christophe; Suh, Yousin; Canaud, Guillaume.

In: Kidney International, 01.01.2018.

Research output: Contribution to journalArticle

Johnson, SC, Martinez, F, Bitto, A, Gonzalez, B, Tazaerslan, C, Cohen, C, Delaval, L, Timsit, J, Knebelmann, B, Terzi, F, Mahal, T, Zhu, Y, Morgan, PG, Sedensky, MM, Kaeberlein, M, Legendre, C, Suh, Y & Canaud, G 2018, 'mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases', Kidney International. https://doi.org/10.1016/j.kint.2018.08.038
Johnson, Simon C. ; Martinez, Frank ; Bitto, Alessandro ; Gonzalez, Brenda ; Tazaerslan, Cagdas ; Cohen, Camille ; Delaval, Laure ; Timsit, José ; Knebelmann, Bertrand ; Terzi, Fabiola ; Mahal, Tarika ; Zhu, Yizhou ; Morgan, Philip G. ; Sedensky, Margaret M. ; Kaeberlein, Matt ; Legendre, Christophe ; Suh, Yousin ; Canaud, Guillaume. / mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases. In: Kidney International. 2018.
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