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Updated: May 27, 2026
Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess
Published on: June 1, 2022
VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis
Kurt J De Vos1, Gábor M Mórotz, Radu Stoica
1Department of Neuroscience, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London, London SE5 8AF, UK. kurt.de_vos@kcl.ac.uk
Abstract:
A proline to serine substitution at position 56 in the gene encoding vesicle-associated membrane protein-associated protein B (VAPB) causes some dominantly inherited familial forms of motor neuron disease including amyotrophic lateral sclerosis (ALS) type-8. VAPB is an integral endoplasmic reticulum (ER) protein whose amino-terminus projects into the cytosol. Overexpression of ALS mutant VAPBP56S disrupts ER structure but the mechanisms by which it induces disease are not properly understood. Here we show that VAPB interacts with the outer mitochondrial membrane protein, protein tyrosine phosphatase-interacting protein 51 (PTPIP51). ER and mitochondria are both stores for intracellular calcium (Ca(2+)) and Ca(2+) exchange between these organelles occurs at regions of ER that are closely apposed to mitochondria. These are termed mitochondria-associated membranes (MAM). We demonstrate that VAPB is a MAM protein and that loss of either VAPB or PTPIP51 perturbs uptake of Ca(2+) by mitochondria following release from ER stores. Finally, we demonstrate that VAPBP56S has altered binding to PTPIP51 and increases Ca(2+) uptake by mitochondria following release from ER stores. Damage to ER, mitochondria and Ca(2+) homeostasis are all seen in ALS and we discuss the implications of our findings in this context.
Insights
A mutation in VAPB protein causes familial ALS. This study reveals VAPB interacts with PTPIP51 at ER-mitochondria contact sites, impacting calcium signaling and potentially contributing to ALS pathogenesis.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Familial forms of amyotrophic lateral sclerosis (ALS) type-8 are linked to a proline to serine substitution at position 56 in the vesicle-associated membrane protein-associated protein B (VAPB) gene.
- VAPB is an endoplasmic reticulum (ER) protein; its overexpression in ALS mutants disrupts ER structure, but the underlying disease mechanisms remain unclear.
- ER and mitochondria are critical for intracellular calcium (Ca2+) storage and exchange, particularly at mitochondria-associated membranes (MAM).
Purpose of the Study:
- To investigate the interaction between VAPB and mitochondrial proteins.
- To elucidate the role of VAPB in calcium homeostasis at MAM.
- To understand how the ALS-associated VAPB mutation (VAPB-P56S) affects its interaction with PTPIP51 and calcium handling.
Main Methods:
- Investigated the interaction between VAPB and protein tyrosine phosphatase-interacting protein 51 (PTPIP51).
- Determined VAPB localization at mitochondria-associated membranes (MAM).
- Assessed the impact of VAPB or PTPIP51 loss on mitochondrial Ca2+ uptake.
- Analyzed the binding affinity of VAPB-P56S to PTPIP51 and its effect on mitochondrial Ca2+ uptake.
Main Results:
- VAPB interacts with the outer mitochondrial membrane protein PTPIP51.
- VAPB is localized to MAM, and its absence, or the absence of PTPIP51, disrupts mitochondrial Ca2+ uptake from the ER.
- The ALS-associated VAPB-P56S mutation alters its binding to PTPIP51 and enhances mitochondrial Ca2+ uptake.
Conclusions:
- VAPB plays a role in regulating Ca2+ transfer between the ER and mitochondria at MAM.
- The VAPB-P56S mutation disrupts VAPB-PTPIP51 interaction and alters Ca2+ homeostasis, potentially contributing to ER and mitochondrial damage observed in ALS.
- These findings offer insights into the molecular mechanisms underlying ALS pathogenesis, highlighting the importance of ER-mitochondria communication and calcium signaling.
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