DRP1 mutations associated with EMPF1 encephalopathy alter mitochondrial membrane potential and metabolic programs

Author:

Robertson Gabriella L.1ORCID,Riffle Stellan1,Patel Mira1,Bodnya Caroline1,Marshall Andrea2,Beasley Heather K.2ORCID,Garza-Lopez Edgar2,Shao Jianqiang3,Vue Zer2,Hinton Antentor2,Stoll Maria S.4,de Wet Sholto5,Theart Rensu P.6ORCID,Chakrabarty Ram Prosad7,Loos Ben6,Chandel Navdeep S.78ORCID,Mears Jason A.4,Gama Vivian1910ORCID

Affiliation:

1. Vanderbilt University 1 , Cell and Developmental Biology, Nashville, TN 37232 , USA

2. Vanderbilt University 2 , Molecular Physiology and Biophysics, Nashville, TN 37232 , USA

3. Central Microscopy Research Facility, University of Iowa 3 , Iowa City, IA 52246 , USA

4. Case Western Reserve University 4 , Department of Pharmacology and Center for Mitochondrial Diseases, Cleveland, OH 44106 , USA

5. Stellenbosch University 5 , Department of Physiological Sciences, Matieland, 7602, Stellenbosch , South Africa

6. Stellenbosch University 6 , Department of Electrical and Electronic Engineering, Matieland, 7602, Stellenbosch , South Africa

7. Northwestern University 7 , Feinberg School of Medicine Department of Medicine Division of Pulmonary and Critical Care Medicine, Chicago, IL 60611 , USA

8. Northwestern University 8 , Feinberg School of Medicine Department of Biochemistry and Molecular Genetics, Chicago, IL 60611 , USA

9. Vanderbilt University, Vanderbilt Center for Stem Cell Biology 9 , Nashville, TN 37232 , USA

10. Vanderbilt University, Vanderbilt Brain Institute 10 , Nashville, TN 37232 , USA

Abstract

ABSTRACT Mitochondria and peroxisomes are dynamic signaling organelles that constantly undergo fission, driven by the large GTPase dynamin-related protein 1 (DRP1; encoded by DNM1L). Patients with de novo heterozygous missense mutations in DNM1L present with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF1) – a devastating neurodevelopmental disease with no effective treatment. To interrogate the mechanisms by which DRP1 mutations cause cellular dysfunction, we used human-derived fibroblasts from patients who present with EMPF1. In addition to elongated mitochondrial morphology and lack of fission, patient cells display lower coupling efficiency, increased proton leak and upregulation of glycolysis. Mitochondrial hyperfusion also results in aberrant cristae structure and hyperpolarized mitochondrial membrane potential. Peroxisomes show a severely elongated morphology in patient cells, which is associated with reduced respiration when cells are reliant on fatty acid oxidation. Metabolomic analyses revealed impaired methionine cycle and synthesis of pyrimidine nucleotides. Our study provides insight into the role of mitochondrial dynamics in cristae maintenance and the metabolic capacity of the cell, as well as the disease mechanism underlying EMPF1.

Funder

National Institutes of Health

Northwestern University

Howard Hughes Medical Institute

Publisher

The Company of Biologists

Subject

Cell Biology

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