Mitochondrial Enzyme Deficiencies in Neurodegenerative Disorders

Neurodegenerative disorders often stem from impaired mitochondrial function, where enzyme deficiencies compromise energy production, redox balance and organellar integrity. Defects in key dehydrogenases—such as 17β-hydroxysteroid dehydrogenase type 10 and mitochondrial acetoacetyl-CoA thiolase—disrupt fatty acid and steroid metabolism, leading to accumulation of toxic intermediates, calcium dysregulation and activation of apoptotic cascades. Beyond their catalytic roles, these enzymes participate in mitochondrial RNA processing and permeability pore control, underscoring a broader influence on organelle dynamics and cell survival. Genetic studies have uncovered a spectrum of pathogenic variants with variable clinical severity, while biochemical research reveals how post-translational modifications and protein–protein interactions modulate enzyme function. Together, these insights highlight mitochondrial enzyme deficiencies as central contributors to Alzheimer’s, Parkinson’s and related neurodegenerative diseases, and they point to metabolic regulation as a promising therapeutic avenue.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Mitochondrial Enzyme Deficiencies in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in mitochondrial enzyme deficiencies in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

17β-Hydroxysteroid dehydrogenase type 10 (HSD10): A mitochondrial enzyme that oxidises hydroxyacyl-CoAs and contributes to steroid metabolism, tRNA maturation and organelle integrity.

Acetoacetyl-CoA thiolase (T2): A mitochondrial enzyme catalysing the final step of fatty acid β-oxidation and isoleucine degradation; its deficiency leads to ketoacid accumulation and metabolic crises.

Sirtuin 3 (SIRT3): A mitochondrial NAD⁺-dependent deacetylase that regulates enzyme function and mitochondrial dynamics by removing acetyl groups from lysine residues.

Amyloid β-peptide: A cleavage product of amyloid precursor protein that aggregates in Alzheimer’s disease and interacts with mitochondrial proteins to induce neurotoxicity.

References

1. Involvement of Type 10 17β-Hydroxysteroid Dehydrogenase in the Pathogenesis of Infantile Neurodegeneration and Alzheimer’s Disease. International Journal of Molecular Sciences (2023).
2. C‑3 Steroidal Hemiesters as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 10. ACS Omega (2024).
3. A non‐enzymatic function of 17β‐hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. EMBO Molecular Medicine (2010).
4. A Human Brain l-3-Hydroxyacyl-coenzyme A Dehydrogenase Is Identical to an Amyloid β-Peptide-binding Protein Involved in Alzheimer's Disease*. Journal of Biological Chemistry (1998).
5. Deacetylation of HSD17B10 by SIRT3 regulates cell growth and cell resistance under oxidative and starvation stresses. Cell Death & Disease (2020).