Restoring Cell Energy by Stopping the Spread of Damaged Mitochondria

The Problem

Aging creates an accumulation of mutations in the DNA of our mitochondria, the organelles that create our energy supply on a molecular level. This impacts and impairs their ability to function correctly and creates a myriad of energy issues as we age. The most prevalent and dangerous types of mutations are the large deletions of DNA – which completely take over the cell and outcompete healthy mitochondria through a mechanism that hides them in plain sight.

The Goal

To prevent cells from being overrun by highly mutated mitochondria, the mechanism that cloaks them from detection and removal needs to be found and countered.

The Status

A mechanism has been found for this ability of the mutated mitochondria to hide and spread and a class of drugs has been identified to inhibit it. The most promising drug improves the removal of mutated mitochondria seemingly by targeting specifically the deletion mutation that is most prevalent.

Restoring Mitophagy Surveillance to mtDNA Deletion-Bearing Mitochondria

The most prevalent mitochondrial mutations in aging cells — and the ones most closely linked to diseases of aging — are large deletions in the genome. A surprising feature of these mutations is that in cells where they occur, mitochondria bearing large deletions are homoplasmic within the cell, pointing to clonal expansion having outcompeted both healthy mitochondrial genomes and mitochondria bearing only minor mutations in one or a few specific mitochondrial genes. The best-supported mechanistic explanation for this finding is that deletion-bearing mutations escape surveillance by the mitophagy machinery, likely due to the absence of signals that are closely linked to the operation of the respiratory machinery that would otherwise attract key components of the mitophagy machinery. This project aims to use small molecules to inhibit a target that allows deletion-bearing mitochondria to survive without attracting these mitophagy components, thus eliminating the selection advantage underlying their clonal expansion.

Promisingly, one of three candidates elicited a substantial shift in favor of wild-type mitochondrial genomes in a cell line heteroplasmic for the common age-related deletion, while only causing a minor favorable shift in heteroplasmy in a point mutation cybrid line. This differential effect is consistent with the mitophagy-avoidance mechanism that has been hypothesized to underlie large deletion mutations’ clonal expansion. The Boominathan lab is now conducting additional studies to confirm the mechanism and to identify or develop drug variants with improved biochemical efficacy.

The goal of this project is to determine how we might achieve optimal parameters for coding and non-coding regions to efficiently express and target the 13 mtDNA genes to the respiratory chain from the nucleus. Toward this end, we employ molecular biology, biochemistry and computational strategies, and refine and build on our existing knowledge of import conditions for the numerous nuclear mitochondrial proteins already delineated. We use patient-derived cybrids and animal models in assessing the functional utility of our constructs. Ultimately, we aim to express the mtDNA genes individually or in combination to overcome age-related changes to the mtDNA and improve overall organelle fitness. Please see here for recent progress on this project.

Team Members

Please visit the Work With Us page to learn about available positions.


Amutha Boominathan, PhD

Principal Investigator


Annual Budget
280,000 USD

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