Membrane Contact Site Dysfunction Module

Neuroscience Metabolism Module membrane_contact_site_dysfunction 10 disorders Pathograph 8

A conserved organelle-communication module. Organelles exchange lipids, calcium and signals at membrane contact sites, places where two membranes are held a few tens of nanometres apart by tethering proteins without fusing. Every organelle forms such contacts, so the module is written for any organelle pair: ER-mitochondria, ER-plasma membrane, ER-Golgi, ER-lipid droplet, ER-peroxisome, ER-endolysosome and mitochondria-lysosome. The chain runs from loss of a tether or contact-resident transfer protein, to failed or mis-regulated non-vesicular lipid transfer between the two organelles (the key conformance target), with a parallel arm for failed calcium transfer at ER-mitochondria contacts. The lipid arm leaves one or both organelles with the wrong membrane composition, most clearly the plasmalogen ether-phospholipid deficit that follows loss of the ACBD5-VAP tether between peroxisomes and the ER. Both arms, and the loss of tethering itself, change organelle morphology, number and position, which is also what multispectral organelle imaging ("organelle signature" analysis) measures. Lipid supply and organelle maturation at contacts are needed to build synapses, so synapse formation is a distinct downstream step. The main terminal consequence is neural: the conforming disorders are overwhelmingly neurodevelopmental, neurodegenerative or neuromuscular. A second, model-system consequence is impaired cardiomyocyte differentiation and maturation, through sarcoplasmic reticulum-mitochondria calcium coupling and through mitochondrial fusion, which Golgi-derived phosphoinositide vesicles help drive at mitofusin-marked sites. Complementary to `mitochondrial_dysfunction` (failure inside the mitochondrion), `peroxisomal_metabolic_failure` (failure of peroxisomal import or enzymes) and `lysosomal_substrate_accumulation`; this module covers the failure of the connection between organelles, not of either organelle's own machinery.

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Pathophysiology Nodes

8 shared nodes are defined in this module.

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Cell Types

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Biological Processes

organelle localization by membrane tethering GO:0140056 ↓ DECREASED intermembrane lipid transfer GO:0120009 ↕ DYSREGULATED calcium import into the mitochondrion GO:0036444 ↓ DECREASED lipid homeostasis GO:0055088 ↕ DYSREGULATED plasmalogen (ether lipid) biosynthesis GO:0008611 ↓ DECREASED organelle organization GO:0006996 ⚠ ABNORMAL synapse assembly GO:0007416 ↓ DECREASED cardiac muscle cell differentiation GO:0055007 ↓ DECREASED

Notes

This is a shared mechanism module, not a disease. Do not create a "membrane contact site disease" Disease entry. Disorder-specific substitutions at the trigger node are the tether or contact-resident protein and the organelle pair it joins. Worked examples already in the knowledge base: VAPB, the ER-side tether for FFAT-motif partners (Adult-Onset_Proximal_Spinal_Muscular_Atrophy_Autosomal_Dominant); VPS13A, bridging the ER to mitochondria and lipid droplets (Chorea-acanthocytosis), and its XK partner at ER-plasma membrane contacts (McLeod_Neuroacanthocytosis_Syndrome); wolframin and CISD2 at mitochondria-associated ER membranes (Wolfram_Syndrome, WFS1-Related_Disorder); PDZD8 at ER-mitochondria and ER-lysosome contacts (Intellectual_Developmental_Disorder_With_Autism_And_Dysmorphic_Facies); SNX14 at ER-lipid droplet contacts (Autosomal_Recessive_Spinocerebellar_Ataxia_20); CERT1 at ER-Golgi contacts (Intellectual_Disability_Autosomal_Dominant_34); and ACBD5, the peroxisome-side partner of VAPA/VAPB, at ER-peroxisome contacts (ACBD5_Deficiency, also called retinal dystrophy with leukodystrophy). MFN2 at ER-mitochondria contacts (Charcot-Marie-Tooth type 2A) is a candidate, not yet conformed: that entry has no node for the tethering defect itself. GO has no separate plasmalogen biosynthesis term: "plasmalogen biosynthetic process" is a listed synonym of GO:0008611 ether lipid biosynthetic process, which is the term bound here. An OLS search of GO for "plasmalogen" (2026-10-23) returned only GO:0008611, GO:0046485 ether lipid metabolic process, and two molecular-function terms. The central node is deliberately "disrupted" rather than "reduced" transfer. The CERT1 autoregulatory-domain variants of Intellectual_Disability_Autosomal_Dominant_34 run ER-to-Golgi ceramide transfer above its regulated level; that is a contact-site transfer defect of the opposite sign and conforms at the same node. Conformance requires evidence that the disorder's protein acts at a contact site and that its loss changes contact extent, transfer, or both. Expression of a gene at the ER or in mitochondria is not sufficient, and neither is a mitochondrial or peroxisomal defect on its own: those belong to the organelle-intrinsic modules named in the description. Several conformers co-annotate with those modules, which is expected. The morphology node is both a consequence and the main observable. A mitofusin, atlastin or DRP1 defect changes organelle shape without being a contact-site defect; such entries do not conform here through the morphology node alone. Not an Xogenesis module: no pathological anatomical entity is formed.

Discussions and Knowledge Gaps

Do contact-site disorders produce a characteristic organelle signature in the affected human cell type, and does it explain why neurons rather than other cells are damaged?

KNOWLEDGE GAP OPEN mcs_neuronal_vulnerability_organelle_signature

Attached to: Altered Organelle Morphology, Number and Distribution Neural Cell Dysfunction from Contact-Site Failure

Most of the evidence in this module comes from single organelle pairs in non-neural cell lines. Neurons and astrocytes have different baseline organelle profiles, and contacts are rewired during neuronal differentiation, so a defect measured in HeLa or COS-7 cells may not show what goes wrong in the cell that degenerates. Contacts between different pairs also share tethers (VAPB serves several), so a single-pair assay can miss the effect on the rest of the network.

Proposed experiments: Organelle signature analysis of contact-site disorder iPSC-derived neurons and glia

Do direct Golgi-mitochondria contacts exist in cardiomyocytes, and do they change as cardiomyocytes differentiate and mature?

KNOWLEDGE GAP OPEN mcs_golgi_mitochondria_cardiomyocyte

Attached to: Altered Organelle Morphology, Number and Distribution Impaired Cardiomyocyte Differentiation and Maturation

The cardiac evidence for Golgi-mitochondria communication is indirect: Golgi-derived vesicles carrying PI(4)P or PI(3,4)P2 reach ER-mitochondria and mitofusin-marked sites to complete mitochondrial division or fusion, and deleting the PI(3,4)P2-producing kinases in cardiomyocytes fragments mitochondria and causes heart failure. That is a vesicle acting at a three-organelle contact, not a stable two-membrane contact. Stable, long-lived Golgi-mitochondria contacts have been described in pancreatic acinar cells, where they shape Golgi calcium gradients, but no tether is known and they have not been mapped in heart muscle. Whether the Golgi is a regulated contact partner of mitochondria during cardiomyocyte maturation, or only a source of signalling vesicles, is open.

Proposed experiments: Organelle signature time course of iPSC-cardiomyocyte differentiation

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Used By Disorder Entries

ACBD5 Deficiency via Loss of Peroxisome-ER Membrane Contacts → Loss of Organelle Tethering at a Membrane Contact Site , Disturbed Ether Lipid Synthesis → Organelle Membrane Lipid Imbalance , Altered Peroxisome Abundance and Motility → Altered Organelle Morphology, Number and Distribution

Adult-Onset Proximal Spinal Muscular Atrophy, Autosomal Dominant via Loss of Functional VAPB at ER Membrane Contact Sites → Loss of Organelle Tethering at a Membrane Contact Site , Disrupted ER-Mitochondria Contact and Calcium Handling → Impaired Inter-Organelle Calcium Transfer

Autosomal Recessive Spinocerebellar Ataxia 20 via Abnormal Lipid Droplet Maturation → Altered Organelle Morphology, Number and Distribution

Chorea-acanthocytosis via Membrane Contact Site Dysfunction with Impaired Lipid Transport → Disrupted Non-Vesicular Lipid Transfer Between Organelles

Intellectual Developmental Disorder With Autism And Dysmorphic Facies via Impaired ER-Mitochondria Calcium Coupling → Impaired Inter-Organelle Calcium Transfer

Intellectual Disability Autosomal Dominant 34 via Excess ER-to-Golgi Ceramide Transfer → Disrupted Non-Vesicular Lipid Transfer Between Organelles

McLeod Neuroacanthocytosis Syndrome via Loss of XK-VPS13A Phospholipid Scrambling at Membrane Contact Sites → Disrupted Non-Vesicular Lipid Transfer Between Organelles

SLC25A46-Related Hereditary Motor And Sensory Neuropathy via Impaired Interorganellar Lipid Transfer at ER-Mitochondria Contacts → Disrupted Non-Vesicular Lipid Transfer Between Organelles , Altered Mitochondrial Phospholipid Composition → Organelle Membrane Lipid Imbalance

WFS1-Related Disorder via Loss of Endoplasmic Reticulum Calcium Homeostasis and MAM Integrity → Impaired Inter-Organelle Calcium Transfer

Wolfram Syndrome via ER-Mitochondria Contact and Calcium Transfer Dysregulation → Impaired Inter-Organelle Calcium Transfer

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.

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Pathophysiology

Loss of Organelle Tethering at a Membrane Contact Site

trigger

A tethering protein that holds two organelle membranes in apposition, or a protein resident at that apposition, is lost or altered, and the contact between the two organelles shrinks or fails to form. Contacts are ubiquitous, so the organelle pair is set by the conforming disorder.

organelle localization by membrane tethering GO:0140056 ↓ DECREASED

organelle membrane contact site GO:0044232

Used by disorders

ACBD5 Deficiency as Loss of Peroxisome-ER Membrane Contacts

Adult-Onset Proximal Spinal Muscular Atrophy, Autosomal Dominant as Loss of Functional VAPB at ER Membrane Contact Sites

Downstream

Disrupted Non-Vesicular Lipid Transfer Between Organelles Without the tether, lipid transfer across the contact fails or loses its regulation.
Impaired Inter-Organelle Calcium Transfer At ER-mitochondria contacts, loss of tethering lowers mitochondrial calcium uptake.
Altered Organelle Morphology, Number and Distribution Untethered organelles change shape and move more.

Show evidence (4 references)

PMID:31732717 SUPPORT REVIEW SYNTHESIS Other

"Interest in MCSs has grown dramatically in the past decade as it is has become clear that they are ubiquitous and have a much broader range of critical roles in cells than was initially thought."

Review establishing that contact sites occur throughout the cell, which is why the trigger is written for any organelle pair.

PMID:19052620 SUPPORT In vitro / ex vivo

"Thus, mitofusin 2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca(2+) uptake."

Identifies a disease gene product as an ER-mitochondria tether, the first worked instance of the trigger.

PMID:28108524 SUPPORT In vitro / ex vivo

"We show that ACBD5-VAPB interaction regulates PO-ER associations."

Establishes the ACBD5-VAPB pair as the peroxisome-ER tether.

+ 1 more reference

Disrupted Non-Vesicular Lipid Transfer Between Organelles

central effector

The key conformance target. Lipid transfer proteins working at contacts move lipids between organelles that are not connected by vesicle traffic. When the contact or the transfer protein fails, or escapes its regulation, lipid flux between the two membranes is lost or set at the wrong level.

intermembrane lipid transfer GO:0120009 ↕ DYSREGULATED

organelle membrane contact site GO:0044232

Used by disorders

Chorea-acanthocytosis as Membrane Contact Site Dysfunction with Impaired Lipid Transport

Intellectual Disability Autosomal Dominant 34 as Excess ER-to-Golgi Ceramide Transfer

McLeod Neuroacanthocytosis Syndrome as Loss of XK-VPS13A Phospholipid Scrambling at Membrane Contact Sites

SLC25A46-Related Hereditary Motor And Sensory Neuropathy as Impaired Interorganellar Lipid Transfer at ER-Mitochondria Contacts

Downstream

Organelle Membrane Lipid Imbalance Failed transfer leaves the donor or acceptor membrane with the wrong lipid composition.

Show evidence (2 references)

PMID:30093493 SUPPORT In vitro / ex vivo

"We also show that human VPS13A and VPS13C bind to the ER, tethering it to mitochondria (VPS13A), to late endosome/lysosomes (VPS13C), and to lipid droplets (both VPS13A and VPS13C)."

The proteins mutated in chorea-acanthocytosis and Parkinson disease are contact-site tethers for several organelle pairs.

PMID:30093493 SUPPORT In vitro / ex vivo

"These findings identify VPS13 as a lipid transporter between the ER and other organelles, implicating defects in membrane lipid homeostasis in neurological disorders resulting from their mutations."

Identifies lipid transport at the contact as the function lost in VPS13 disease.

Impaired Inter-Organelle Calcium Transfer

effector

At ER-mitochondria contacts, calcium released from ER stores is taken up by mitochondria. Loss of the contact or of its calcium-handling partners reduces that transfer, with consequences for mitochondrial metabolism and for cytosolic calcium buffering in neurons.

calcium import into the mitochondrion GO:0036444 ↓ DECREASED

mitochondria-associated endoplasmic reticulum membrane contact site GO:0044233

Used by disorders

Adult-Onset Proximal Spinal Muscular Atrophy, Autosomal Dominant as Disrupted ER-Mitochondria Contact and Calcium Handling

Intellectual Developmental Disorder With Autism And Dysmorphic Facies as Impaired ER-Mitochondria Calcium Coupling

WFS1-Related Disorder as Loss of Endoplasmic Reticulum Calcium Homeostasis and MAM Integrity

Wolfram Syndrome as ER-Mitochondria Contact and Calcium Transfer Dysregulation

Downstream

Neural Cell Dysfunction from Contact-Site Failure Reduced mitochondrial calcium uptake impairs neuronal calcium handling and metabolism.
Impaired Cardiomyocyte Differentiation and Maturation In cardiomyocytes the ER is the sarcoplasmic reticulum, and its coupling to mitochondria through the IP3R-GRP75-VDAC bridge is needed for maturation.

Show evidence (1 reference)

PMID:19052620 SUPPORT In vitro / ex vivo

"Juxtaposition between endoplasmic reticulum (ER) and mitochondria is a common structural feature, providing the physical basis for intercommunication during Ca(2+) signalling"

Establishes ER-mitochondria apposition as the route for calcium transfer.

Organelle Membrane Lipid Imbalance

effector

One or both organelles end up with the wrong lipid composition. The clearest case is ether-phospholipid synthesis, which starts in the peroxisome and is completed in the ER, so plasmalogen production depends on ER-peroxisome contact. Other conformers show lipid droplet, sphingolipid or cholesterol imbalance, according to the organelle pair.

lipid homeostasis GO:0055088 ↕ DYSREGULATED plasmalogen (ether lipid) biosynthesis GO:0008611 ↓ DECREASED

Used by disorders

ACBD5 Deficiency as Disturbed Ether Lipid Synthesis

SLC25A46-Related Hereditary Motor And Sensory Neuropathy as Altered Mitochondrial Phospholipid Composition

Downstream

Altered Organelle Morphology, Number and Distribution Organelles built from the wrong lipids grow, divide and mature abnormally.
Impaired Synapse Formation and Maturation Developing synapses depend on contact-supplied lipids such as plasmalogens.

Show evidence (2 references)

PMID:28108526 SUPPORT In vitro / ex vivo

"We also demonstrate that tethering of peroxisomes to the ER is necessary for peroxisome growth, the synthesis of plasmalogen phospholipids, and the maintenance of cellular cholesterol levels."

Contact loss causes plasmalogen and cholesterol imbalance.

PMID:41726917 SUPPORT In vitro / ex vivo

"Disrupting this contact impairs plasmalogen production, synaptic organization, and neuronal activity"

In human iPSC-derived neurons, disrupting ER-peroxisome contact lowers plasmalogen production. Preprint, not yet peer reviewed.

Altered Organelle Morphology, Number and Distribution

effector

Organelles that lose a contact change size, shape, number, position and movement. This node is also the main observable: multispectral imaging of six to eight organelles at once in live cells measures their morphology, distribution and pairwise or higher-order contacts together, so a contact defect and its morphological consequence can be read in one experiment.

organelle organization GO:0006996 ⚠ ABNORMAL

Used by disorders

ACBD5 Deficiency as Altered Peroxisome Abundance and Motility

Autosomal Recessive Spinocerebellar Ataxia 20 as Abnormal Lipid Droplet Maturation

Downstream

Neural Cell Dysfunction from Contact-Site Failure Neurons depend on correctly sized and positioned organelles in long processes.
Impaired Cardiomyocyte Differentiation and Maturation Mitochondrial fusion and network shape, set in part at ER-mitochondria and Golgi-mitochondria interfaces, direct cardiomyocyte differentiation. The fusion evidence supports this edge indirectly; the evidence specific to contact sites is on the calcium edge.
Impaired Synapse Formation and Maturation Contact-dependent organelle maturation, such as lysosome maturation at ER-lysosome contacts, supplies the autophagic capacity that activity-driven synaptic growth needs.

Show evidence (4 references)

PMID:19052620 SUPPORT In vitro / ex vivo

"Ablation or silencing of mitofusin 2 in mouse embryonic fibroblasts and HeLa cells disrupts ER morphology"

Loss of an ER-mitochondria tether changes ER morphology.

PMID:32193326 SUPPORT In vitro / ex vivo

"Here, we found that microdomains of phosphatidylinositol 4-phosphate ... on trans-Golgi network (TGN) vesicles were recruited to mitochondria-ER contact sites and could drive mitochondrial division downstream of Drp1."

Golgi-mitochondria communication shapes mitochondria: trans-Golgi vesicles join ER-mitochondria contacts, a three-organelle contact, to complete mitochondrial division.

PMID:42848893 SUPPORT In vitro / ex vivo

"Here, we identified a role for Golgi-derived vesicles enriched in phosphatidylinositol 3,4-bisphosphate ... in regulating mitochondrial fusion. We found that these vesicles were recruited to ER- and mitofusin-marked fusion sites."

A second population of Golgi-derived vesicles acts at ER- and mitofusin-marked sites to drive mitochondrial fusion.

+ 1 more reference

Impaired Synapse Formation and Maturation

effector

Building synapses places a high demand on organelle communication. Contacts supply lipids to the growing synaptic membrane (ER-peroxisome contacts and plasmalogens) and the degradative capacity for activity-driven synaptic growth (ER-lysosome contacts and autophagy). Losing either leaves synapses fewer, smaller or disorganized, which fits the intellectual disability and epilepsy seen in several conforming disorders.

neuron CL:0000540

synapse assembly GO:0007416 ↓ DECREASED

Downstream

Neural Cell Dysfunction from Contact-Site Failure Too few or disorganized synapses impair neuronal activity and circuit development.

Show evidence (2 references)

PMID:41726917 SUPPORT In vitro / ex vivo

"Later, endoplasmic reticulum (ER)-organelle contacts dominate with ER-peroxisome contacts promoting ether lipid biosynthesis, membrane homeostasis and synapse formation."

In human iPSC-derived neurons, ER-peroxisome contacts promote synapse formation. Preprint.

PMID:40156832 SUPPORT Model organism

"We find that PDZD8 is required for activity-dependent synaptic bouton formation in multiple paradigms."

In Drosophila, the contact-site tether PDZD8 is required for synaptic bouton formation.

Neural Cell Dysfunction from Contact-Site Failure

consequence

The conforming disorders are almost all neurological: motor neuron disease, neuropathy, spastic paraplegia, ataxia, chorea, leukodystrophy and neurodevelopmental disorders. Neurons have a distinctive organelle profile dominated by mitochondria, and they respond to stress with larger organelle changes than astrocytes do. Why neurons are the vulnerable cell type is an open question (see discussions).

neuron CL:0000540

Show evidence (3 references)

PMID:30093493 SUPPORT BACKGROUND Human clinical

"Mutations in the human VPS13 genes are responsible for neurodevelopmental and neurodegenerative disorders including chorea acanthocytosis (VPS13A) and Parkinson's disease (VPS13C)."

Contact-site lipid transporters are mutated in neurological disease.

PMID:19052620 SUPPORT BACKGROUND Human clinical

"mitofusin 2, a mitochondrial dynamin-related protein mutated in the inherited motor neuropathy Charcot-Marie-Tooth type IIa, is enriched at the ER-mitochondria interface"

An ER-mitochondria tether is the gene mutated in an inherited motor neuropathy.

PMID:40956669 SUPPORT In vitro / ex vivo

"Neurons are characterized by prominent mitochondrial composition and interactions, while astrocytes contain more lysosomes and lipid droplet interactions. Additionally, neurons display a more robust organelle response than astrocytes to acute oxidative or ER stress."

Organelle signature analysis in primary rodent neural cells shows that neurons rely on mitochondrial contacts and react more strongly to stress, one candidate reason for neuronal vulnerability.

Impaired Cardiomyocyte Differentiation and Maturation

consequence

The second cell type in which contact-site failure has a measured developmental consequence. Cardiomyocytes build a dense mitochondrial network coupled to the sarcoplasmic reticulum. Loss of mitofusin-mediated fusion and tethering, of SR-mitochondria calcium coupling, or of the Golgi-derived phosphoinositide vesicles that act at mitofusin-marked fusion sites blocks or distorts cardiomyocyte differentiation and maturation, and in mice leads to arrested heart development or heart failure. The evidence is from mouse hearts and mouse embryonic stem cell-derived cardiomyocytes; no human contact-site disorder in the knowledge base yet carries a cardiac node that conforms here.

cardiac muscle cell CL:0000746

cardiac muscle cell differentiation GO:0055007 ↓ DECREASED

Show evidence (2 references)

PMID:24091702 SUPPORT Model organism

"We found that mitochondrial fusion was required for proper cardiomyocyte development."

Mitochondrial fusion, which mitofusins also tie to ER contacts, is required for cardiomyocyte development.

PMID:41848670 SUPPORT In vitro / ex vivo

"MFN2 knockdown caused detrimental effects on mESC-CM maturation in terms of structure, cytosolic calcium kinetics, electrophysiology, and metabolism."

Losing the SR-mitochondria tether MFN2 impairs maturation of ESC-derived cardiomyocytes.