HPDL deficiency causes a neuromuscular disease by impairing the mitochondrial respiration

Area of Science:

• Genetics
• Neuroscience
• Mitochondrial Biology

Background:

• Mitochondrial diseases stem from genetic variations in nuclear and mitochondrial DNA.
• The nuclear gene HPDL, encoding a mitochondrial intermembrane protein, is linked to pediatric neurodegenerative disorders with spasticity.
• Previous research suggests HPDL's involvement in specific movement disorders.

Purpose of the Study:

• To expand the understanding of the clinical and genetic spectrum of HPDL-related mitochondrial neuropathy.
• To investigate the functional consequences of HPDL variants on mitochondrial function.
• To elucidate the molecular mechanisms underlying HPDL-associated neurodegeneration.

Main Methods:

• Clinical evaluation of six Chinese patients from four families with suspected HPDL-related neuropathy.
• Identification and characterization of bi-allelic HPDL pathogenic variants using genetic sequencing.
• Assessment of mitochondrial respiratory function, including oxygen consumption rate and oxidative phosphorylation (OXPHOS) complex II activity, in patient-derived cells and HPDL-knockdown HeLa cells.
• Rescue experiments involving wild-type HPDL gene overexpression in knockdown cells.

Main Results:

• Six patients presented with variable neuropathic symptoms, including developmental delay, spasm, and hypertonia, linked to bi-allelic HPDL variants.
• Seven distinct pathogenic HPDL variants were identified, with five being novel.
• Patient-derived cells and HPDL-knockdown cells exhibited impaired mitochondrial respiration and reduced OXPHOS complex II activity.
• Overexpression of wild-type HPDL restored normal respiratory function in knockdown cells.

Conclusions:

• Bi-allelic HPDL variants cause a spectrum of mitochondrial neuropathy with diverse clinical presentations.
• HPDL is essential for normal mitochondrial respiratory chain function, particularly OXPHOS complex II activity.
• These findings broaden the known genetic and clinical landscape of HPDL-related neurodegenerative diseases.