Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency.
JCI Insight
; 9(17)2024 Sep 10.
Article
in En
| MEDLINE
| ID: mdl-39088276
ABSTRACT
Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid ß-oxidation. Mutations in HADHA and HADHB, which encode the TFP α and ß subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting CL metabolism might be dependent on patient genotype.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cardiolipins
/
Energy Metabolism
/
Fibroblasts
/
Mitochondrial Trifunctional Protein, alpha Subunit
/
Lipid Metabolism, Inborn Errors
Limits:
Animals
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Humans
/
Male
Language:
En
Journal:
JCI Insight
Year:
2024
Document type:
Article