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A biallelic MRPL42variant causes a combined oxidative phosphorylation deﬁciency syndrome revealed by multi-omics

ABSTRACT: Pathogenic variants affecting components of the mitochondrial translation machinery lead to various impairments of mitochondrial function and thereby cause a spectrum of multisystem diseases. In an infant with a fatal, metabolic multisystem condition we performed a comprehensive multi-omicsapproach and detected the intronic biallelic variant NM_014050.4:c.219+6 T > A in MRPL42 (mitochondrial ribosomal protein L42) encoding a component of the large mitochondrial ribosomal subunit. RNA-seq revealed a strong reduction and aberrant splicing of the majority of MRPL42 transcripts leading to a frameshift and thereby to a premature termination codon: p.(Asn46Leufs*18). However, additional use of the canonical splice site led to a low residual expression of the wildtype transcript and MRPL42 protein abundance was consequently strongly reduced. Complex I and IV activity of the oxidative phosphorylation (OXPHOS) system were reduced and a decrease of complex I, III, IV, and mitoribosomal-related proteins was identiﬁed by proteomics. Complementation with wildtype MRPL42 corrected most of these phenotypes conﬁrming that they were a direct consequence of the limited availability of MRPL42. Our multi-omics data conﬁrm biallelic MRPL42 loss-of-function as the underlying cause of the fatal mitochondrial disease in our patient. Therefore, we propose MRPL42 deﬁciency as the cause of a mitochondrial ribosome-related combined OXPHOS-deﬁciency syndrome.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

SUBMITTER: David Meierhofer

LAB HEAD: Björn Fischer-Zirnsak

PROVIDER: PXD072978 | Pride | 2026-04-14

REPOSITORIES: Pride

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			Action	DRS
	C1_1_S1-G1_1_5591.d.dia	Other
	C1_1_S1-G1_1_5591.d.dia.quant	Other
	C1_2_S1-H1_1_5592.d.dia	Other
	C1_2_S1-H1_1_5592.d.dia.quant	Other
	C1_3_S1-A2_1_5593.d.dia	Other

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Project description:Mitochondrial disorders show remarkable clinical and genetic heterogeneity, and result from genetic variants in either mitochondrial-encoded or nuclear-encoded genes. CHCHD4 is a component of the mitochondrial import and assembly (MIA) pathway that imports small cysteine-containing substrates such as TIM proteins, complex I and IV subunits and/or assembly factors. We report a child subject with biallelic CHCHD4 variants who presented with severe lactic acidosis, psychomotor and neurological regression. Western blot analysis in subject-derived fibroblasts showed decreased steady-state levels of CHCHD4 and a severe oxidative phosphorylation (OXPHOS) defect. Moreover, diminished assembly of both complexes I and IV was also observed. To demonstrate that the segregating CHCHD4 variants were responsible for the observed biochemical phenotype, we overexpressed wild-type CHCHD4 in control and subject fibroblasts, restoring steady-state levels of complex I and IV proteins and the associated OXPHOS assembly defects. Proteomic studies and Reactome enrichment of the altered proteins pointed to respiratory electron transport and complex I biogenesis as the main dysregulated pathways. More detailed analyses revealed a severe loss of several complex I and IV subunit proteins and/or assembly factors, that were rescued by overexpression of wild-type CHCHD4. CHCHD4 is involved in the import of several other mitochondrial proteins, has numerous targets and interacting factors and has been shown to be involved in the export of iron-sulfur clusters synthesized inside mitochondria, suggesting involvement in several mitochondrial and non-mitochondrial functions. Surprisingly, few of these interacting factors or non-mitochondrial functions were impacted by the observed CHCHD4 defect. In conclusion, our work establishes CHCHD4 deficiency as a new cause of dysregulated mitochondrial protein import, and suggests this gene should be investigated in subjects with this rare form of mitochondrial disease.

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A biallelic MRPL42variant causes a combined oxidative phosphorylation deﬁciency syndrome revealed by multi-omics

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