TOMM70 and Mitochondrial Disease

This summary outlines the association between TOMM70 and mitochondrial disease. Comprehensive evidence from case reports and functional assessments supports a role for TOMM70 in disease etiology. A detailed clinical evaluation of a patient with severe anemia, lactic acidosis, and global developmental delay revealed compound heterozygous mutations in TOMM70, establishing a link between the gene and mitochondrial dysfunction (PMID:31907385). The case report also emphasizes that aberrant mitochondrial protein import is a central pathogenic mechanism.

Genetic evidence is derived from a single proband harboring two compound heterozygous variants, notably including the variant c.794C>T (p.Thr265Met). This variant, together with an additional allele (c.1745C>T (p.Ala582Val)), was identified in a patient whose clinical presentation includes lactic acidosis and developmental delay (PMID:31907385). Although segregation data from extended family members is limited, the presence of these deleterious variants in a patient with a severe clinical phenotype supports their likely pathogenic role.

Detailed genetic assessment indicates that the mutation c.794C>T (p.Thr265Met) disrupts a key region of the TOMM70 protein, compromising its function in mitochondrial protein import. The identification of such variants in an autosomal recessive inheritance pattern underscores the importance of biallelic disruption in disease causation (PMID:31907385). The limited number of probands currently restricts the genetic evidence to a single-case level, but the correlation between the genotype and clinical phenotype is noteworthy.

Extensive functional studies complement the genetic findings. In patient-derived lymphocytes, decreased TOM70 expression and abnormal oligomerization of the TOM complex were observed, leading to multi-oxidative phosphorylation system (OXPHOS) deficits. Rescue experiments in a TOM70 knockdown U2OS cell model confirmed that only wild-type TOM70 could restore complex IV activity and proper protein expression, providing robust functional validation of the variant effects (PMID:31907385, PMID:16803880, PMID:20504278). Additionally, complementary biophysical studies have characterized TOM70’s unfolding and oligomeric states, further illustrating its critical role in mitochondrial import.

No significant conflicting evidence is reported in the literature, and the convergence of clinical genetics and functional data provides a coherent mechanism for TOMM70-related mitochondrial dysfunction. Independent studies reinforce that the proper monomeric form of TOM70 is essential for its function, and deviations from this state contribute to the disease phenotype. This multifaceted evidence, while originating from a single case, is bolstered by strong experimental support, validating the pathogenic role of TOMM70 variants in mitochondrial disease.

In summary, the integrated data from clinical case reports and experimental studies firmly support a disease association between TOMM70 and mitochondrial disease. While the genetic evidence is derived from a single proband, extensive functional validation underlines the biological plausibility of the causal relationship. Key take‑home sentence: TOMM70 mutations, through disruption of mitochondrial protein import and consequent OXPHOS deficits, represent a critical diagnostic marker for mitochondrial disease with actionable implications for future therapeutic strategies.

References

• Journal of human genetics • 2020 • Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay PMID:31907385
• The Journal of biological chemistry • 2006 • Tracking the unfolding pathway of a multirepeat protein via tryptophan scanning: evidence of localized instability in the mitochondrial import receptor Tom70 PMID:16803880
• The Biochemical journal • 2010 • Human mitochondrial import receptor Tom70 functions as a monomer PMID:20504278

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