Mitochondrial phosphopantetheinylation is required for oxidative metabolism
Pieter R Norden1, Riley J Wedan2, Samuel E J Preston1
1Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, United States of America.
Metabolism: Clinical and Experimental
|October 8, 2025
Summary
A newly discovered mitochondrial localization for aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT) is crucial for cellular energy production. This finding explains how mitochondrial fatty acid synthesis supports respiration and identifies potential causes of human disease.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- 4'-Phosphopantetheinyl (4'PP) groups are vital cofactors for numerous enzymes, added by phosphopantetheinyl transferase (PPTase) enzymes.
- While 4'PP-modified proteins exist in mitochondria, a mammalian mitochondrial PPTase remained elusive.
- Mitochondrial respiration and oxidative metabolism rely on specific protein modifications.
Purpose of the Study:
- To identify the mammalian PPTase responsible for mitochondrial 4'PP modification.
- To investigate the role of AASDHPPT in mitochondrial function and metabolism.
- To determine the functional significance of AASDHPPT's localization within the cell.
Main Methods:
- Investigated the role of cytoplasmic AASDHPPT in mitochondrial respiration.
- Analyzed the impact of AASDHPPT loss on 4'PP modification of mitochondrial acyl carrier protein.
- Examined the activity of the mitochondrial fatty acid synthesis (mtFAS) pathway.
- Identified and characterized the mitochondrial targeting sequence of AASDHPPT.
- Assessed the pathogenicity of AASDHPPT variants in humans.
Main Results:
- AASDHPPT is essential for mitochondrial respiration and oxidative metabolism.
- Loss of AASDHPPT impairs 4'PP modification and mtFAS pathway activity.
- AASDHPPT localizes to the mitochondrial matrix via an N-terminal targeting sequence.
- This mitochondrial localization is critical for mtFAS activity and oxidative metabolism.
- Identified five AASDHPPT variants potentially causing pathogenic loss of mtFAS activity.
Conclusions:
- The cytoplasmic enzyme AASDHPPT possesses a novel mitochondrial localization essential for mtFAS activity and oxidative metabolism.
- This discovery elucidates a key mechanism supporting mitochondrial function and energy production in mammals.
- Pathogenic variants in AASDHPPT may lead to human diseases associated with impaired mitochondrial fatty acid synthesis.
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