Aberrant Drp1-mediated mitochondrial division presents in humans with variable outcomes

Area of Science:

• Biochemistry and Molecular Biology
• Cell Biology
• Genetics

Background:

• Mitochondrial dynamics, encompassing division, fusion, and transport, are crucial for cellular health.
• The DNM1L gene encodes dynamin-related protein 1 (Drp1), essential for mitochondrial division.
• De novo mutations in DNM1L are linked to various disease states.

Observation:

• This study identified five patients with pathogenic or likely pathogenic variants in DNM1L, including two novel variants.
• The identified Drp1 variant positions are highly conserved across dynamin-related proteins involved in membrane and organelle division.

Findings:

• Pathogenic variants in DNM1L significantly impair mitochondrial division.
• Novel DNM1L variants contribute to the known spectrum of diseases associated with Drp1 dysfunction.
• Conserved residues in Drp1 variants suggest a fundamental role in its division function.

Implications:

• Expanding the clinical spectrum of DNM1L-associated diseases.
• Provides insights into the molecular mechanisms underlying Drp1-mediated mitochondrial division.
• Highlights the importance of conserved residues for protein function and disease pathogenesis.