# Aberrant ER-mitochondria communication in human mitochondrial disease

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $522,259

## Abstract

Mitochondrial disease, defined as a group of disorders due to defects in the respiratory chain/oxidative-phosphorylation system (OxPhos), comprises an important group of pathologies that are challenging to study
and treat, as they are among the most heterogeneous human conditions at every level: clinical, biochemical,
and genetic. Mitochondria are under dual genetic control, dependent on both nuclear DNA (nDNA) and
mitochondrial DNA (mtDNA). Pathogenic mutations in genes encoded by both genomes give rise to
mitochondrial disease, many of which are neurodegenerative disorders that typically are both devastating and
ultimately fatal. Mutations in mtDNA genes affect structural subunits of the OxPhos system, whereas mutations
in nDNA genes are more numerous and diverse, as they encode not only a large number of OxPhos subunits
but also factors needed for the proper synthesis, assembly, and functioning of the OxPhos machinery.
 We recently discovered that in cells from patients with mitochondrial disease there is a significant
disruption in the intimate communication, both physical and biochemical, between mitochondria and
endoplasmic reticulum (ER) at "mitochondria-associated ER membranes (MAM)". MAM is a central locus for
maintaining cellular cholesterol, phospholipid, and calcium homeostasis, as well as regulating mitochondrial
bioenergetics and dynamics (organellar fusion, fission, and positioning). Based on this finding, we hypothesize
that reductions in oxidative energy metabolism can disrupt ER-mitochondrial communication, with serious
consequences for cell survivability that go well beyond that of reduced ATP output.
 The objectives of this application - and our Specific Aims - are thus threefold: (1) to deduce the genetic and
biochemical circumstances under which OxPhos deficits affect MAM (the "phenotypic landscape"), by
analyzing cells from patients with known mutations in nDNA and mtDNA causing OxPhos deficiency, and by
perturbing bioenergetics with specific OxPhos toxins; (2) to gain insight into the mechanism by which this
occurs, using both biased (i.e. targeted) and unbiased approaches to identify OxPhos-related factors that affect
ER-mitochondrial connectivity; and (3) to determine if we can use either genetic or pharmacological
approaches to improve ER-mitochondrial communication in cells with genetically-compromised bioenergetics,
thereby revealing "latent" OxPhos potential (i.e. improved OxPhos output and efficiency) and increasing
bioenergetic output, even in cells with a high mutation load.
 Our discovery of an "OxPhos-MAM connection" has revealed a hitherto unknown pathogenetic role of
altered inter-organellar communication in mitochondrial disease. In turn, this has opened up a new way of
thinking about the pathogenesis and treatment of mitochondrial disease. A therapeutic strategy based on
"fixing" ER-mitochondrial connectivity to re-normalize MAM function will likely be generalizable to a large
number of mitochondrial disorde...

## Key facts

- **NIH application ID:** 10247029
- **Project number:** 5R01NS117538-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ERIC A. SCHON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $522,259
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247029

## Citation

> US National Institutes of Health, RePORTER application 10247029, Aberrant ER-mitochondria communication in human mitochondrial disease (5R01NS117538-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247029. Licensed CC0.

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