Dual mechanisms found to guard mitochondria against fusion-related damage

Johns Hopkins University School of Medicine researchers have discovered a dual regulatory mechanism safeguarding mitochondrial integrity through the combined actions of Parkin–PINK1 and OMA1. The study reveals that these stress-responsive systems control mitochondrial fusion under normal physiological conditions. Loss of both proteins leads to severe mitochondrial abnormalities, impaired development, and early mortality in mice.

Cells respond to pathogenic and extrinsic stresses through mechanisms that safeguard mitochondrial health. Prior research links impaired mitochondrial stress responses with neurodegeneration, heart failure, and metabolic syndrome. Parkin–PINK1 and OMA1 are known stress sensors activated by mitochondrial dysfunction.

Parkin, an E3 ubiquitin ligase, is recruited to the outer mitochondrial membrane through PINK1 phosphorylation, promoting mitochondrial degradation processes.

OMA1 is a mitochondrial inner membrane protease that inhibits fusion by cleaving the fusion GTPase OPA1. While individually non-essential under normal conditions, the combined loss of Parkin and OMA1 suggests a compensatory relationship between the two systems.

In the study, titled “Dual regulation of mitochondrial fusion by Parkin–PINK1 and OMA1,” published in Nature, researchers analyzed stress sensor loss in eighteen mouse models, including single, double, and triple knockouts.

Systemic homozygous double knockouts of Parkin and OMA1 exhibited small body size, decreased locomotor activity, seizures, and premature death with an average survival of 70 days. Similar phenotypes were observed in Pink1 and OMA1 knockout mice, underscoring the role of Parkin–PINK1 in this mechanism.

Mitochondrial morphology was examined through laser confocal immunofluorescence microscopy in ten brain subregions and eight major organs. Parkin and OMA1 knockout mice displayed enlarged mitochondria, particularly in the brain’s pons/medulla and heart.

Transmission electron microscopy confirmed reduced inner membrane folds in these megamitochondria. Selective reduction of OPA1 or MFN1 significantly rescued mitochondrial abnormalities, survival, and locomotor activity, whereas reduction of MFN2 had no effect.

RNA sequencing of the pons/medulla revealed upregulation of innate immune response genes in Parkin/Oma1 knockout mice. Released mitochondrial DNA (mtDNA) was detected in the cytosol, activating the STING pathway. Triple knockouts, including Stinggt/gt, improved survival and body size, highlighting STING’s role in the observed immune responses.

Metabolomic analysis identified 188 metabolites with no significant differences between wild-type and double knockouts. TCA cycle enzyme activities and mitochondrial respiration rates remained unchanged, indicating that metabolic disruption was not the primary defect.

In the liver, triple knockouts (Alb-Drp1flox/floxParkinflox/floxOma1flox/flox) showed exacerbated mitochondrial enlargement and mitophagy impairment compared to Drp1 knockouts alone. These defects correlated with elevated serum alanine aminotransferase levels, indicating liver damage.

Motor neuron analysis showed reduced neuron counts in the thoracic and lumbar spinal cord of double knockouts, explaining locomotor deficits. Dopaminergic neurons in the substantia nigra and dopamine levels in the striatum were unaffected.

The comprehensive experimental results demonstrate that Parkin–PINK1 and OMA1 control both outer and inner membrane events, compensating for each other when needed (such as when the other is missing) and collaboratively preventing excess mitochondrial fusion while maintaining mitochondrial structure and genome integrity. Loss of both pathways disrupts mitochondrial dynamics, triggering immune responses and organ dysfunction, indicating that the dual regulatory mechanism is critical for animal development, physiology, and survival.

© 2025 Science X Network