Malate-aspartate shuttle (MDH1/MDH2/GOT1/GOT2 + SLC25A11/SLC25A12)

The malate-aspartate shuttle is the principal mechanism by which reducing equivalents (cytosolic NADH generated in glycolysis) are transferred into the mitochondrial matrix for oxidation by the respiratory chain, in tissues such as heart, liver and brain. Because NADH itself cannot cross the inner mitochondrial membrane, the shuttle moves the electrons as malate: in the cytosol, malate dehydrogenase 1 (MDH1) reduces oxaloacetate to malate, consuming a cytosolic NADH; the malate is imported by the oxoglutarate/malate carrier (SLC25A11, OGC) in exchange for 2-oxoglutarate; in the matrix, malate dehydrogenase 2 (MDH2) re-oxidises malate to oxaloacetate, regenerating matrix NADH that feeds Complex I. Oxaloacetate cannot cross the membrane either, so it is transaminated with glutamate to aspartate by mitochondrial aspartate aminotransferase (GOT2, PLP-dependent); the aspartate is exported by the Ca2+-regulated aspartate-glutamate carrier (SLC25A12, AGC1/aralar) in exchange for cytosolic glutamate, and cytosolic aspartate aminotransferase (GOT1) regenerates oxaloacetate and 2-oxoglutarate to close the cycle. The AGC1 antiport, being electrogenic and effectively unidirectional, gives the shuttle its net direction. Defects in these components cause disease: SLC25A12/AGC1 deficiency causes a hypomyelinating encephalopathy (global cerebral hypomyelination / epilepsy), MDH2 and GOT2 deficiencies cause early infantile epileptic encephalopathy, and the shuttle is a key node in cancer redox metabolism.

MODULE:malate_aspartate_shuttleDRAFTMetabolic Pathwaymodules/malate_aspartate_shuttle.yaml
malate-aspartate shuttleGO:0043490
GO:0043490
malate-aspartate shuttle
The module is grounded in the malate-aspartate shuttle (GO:0043490) — transfer of cytosolic reducing equivalents (NADH) into the mitochondrial matrix via malate.
file:human/MDH1/MDH1-ai-review.yaml
MDH1 gene review (human)
The cytosolic malate-dehydrogenase step (UniProtKB:P40925, GO:0030060) matches the completed human MDH1 review.
file:human/GOT1/GOT1-ai-review.yaml
GOT1 gene review (human)
The cytosolic aspartate-aminotransferase step (UniProtKB:P17174, GO:0004069) matches the completed human GOT1 review.
file:human/SLC25A11/SLC25A11-ai-review.yaml
SLC25A11 gene review (human)
The oxoglutarate/malate carrier step (UniProtKB:Q02978, GO:0015367) matches the completed human SLC25A11 review.
file:human/SLC25A12/SLC25A12-ai-review.yaml
SLC25A12 gene review (human)
The aspartate-glutamate carrier (AGC1/aralar) step (UniProtKB:O75746, GO:0000515) matches the completed human SLC25A12 review.
file:human/MDH2/MDH2-ai-review.yaml
MDH2 gene review (human)
The matrix malate-dehydrogenase step (UniProtKB:P40926, GO:0030060) matches the completed human MDH2 review.
file:human/GOT2/GOT2-ai-review.yaml
GOT2 gene review (human)
The matrix aspartate-aminotransferase step (UniProtKB:P00505, GO:0004069) matches the completed human GOT2 review.
4Nodes
3Parts
0Variant Sets
0Variants
6Annotons
3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:malate_aspartate_shuttle deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

6 gene-function check(s) reflected in core functions · 0 conflict(s) · 3 evidence or coverage gap(s) (12 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
mdh1_activity MDH1 (human)
UniProtKB:P40925
Family Representative 		L-malate dehydrogenase (NAD+) activity
GO:0030060 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
got1_activity GOT1 (human)
UniProtKB:P17174
Family Representative 		L-aspartate:2-oxoglutarate transaminase activity
GO:0004069 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
slc25a11_activity SLC25A11 (human)
UniProtKB:Q02978
Family Representative 		oxoglutarate:malate antiporter activity
GO:0015367 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
slc25a12_activity SLC25A12 (human)
UniProtKB:O75746
Family Representative 		aspartate:glutamate, proton antiporter activity
GO:0000515 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mdh2_activity MDH2 (human)
UniProtKB:P40926
Family Representative 		L-malate dehydrogenase (NAD+) activity
GO:0030060 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
got2_activity GOT2 (human)
UniProtKB:P00505
Family Representative 		L-aspartate:2-oxoglutarate transaminase activity
GO:0004069 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mdh1_activity cytosolic malate dehydrogenase (MDH1) family
PANTHER:PTHR23382
Family 		L-malate dehydrogenase (NAD+) activity
GO:0030060 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR23382.
got1_activity aspartate aminotransferase (GOT) family
PANTHER:PTHR11879
Family 		L-aspartate:2-oxoglutarate transaminase activity
GO:0004069 		Family Supported
Family review supports GO:0004069 FAMILY_WIDE. Shared by the cytosolic and mitochondrial eukaryotic isozymes and by bacterial AspC. PAINT places it at the eukaryotic mitochondrial-type node, the cytosolic node and a gammaproteobacterial AspC node. TyrB also transaminates aspartate, but its physiological role is aromatic; the fungal secondary-metabolism members (tasG, ucdG) were not checked. The aspartate/asparagine and malate-aspartate shuttle modules use the family id with compartment-specific representatives, which is appropriate.
slc25a11_activity SLC25A11 / oxoglutarate-malate carrier family
PANTHER:PTHR45618
Family 		oxoglutarate:malate antiporter activity
GO:0015367 		Family Function Unreviewed
The family review has no applicable adjudication supporting or excluding GO:0015367.
slc25a12_activity SLC25A12 / aspartate-glutamate carrier (aralar) family
PANTHER:PTHR45678
Family 		aspartate:glutamate, proton antiporter activity
GO:0000515 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR45678.
mdh2_activity mitochondrial malate dehydrogenase (MDH2) family
PANTHER:PTHR11540
Family 		L-malate dehydrogenase (NAD+) activity
GO:0030060 		Family Supported
Family review supports GO:0030060 FAMILY_WIDE. Asserted by glyoxylate_cycle, malate_aspartate_shuttle, gluconeogenesis and peroxisomal_beta_oxidation (SF72); accepted by every reviewed isozyme.
got2_activity aspartate aminotransferase (GOT) family
PANTHER:PTHR11879
Family 		L-aspartate:2-oxoglutarate transaminase activity
GO:0004069 		Family Supported
Family review supports GO:0004069 FAMILY_WIDE. Shared by the cytosolic and mitochondrial eukaryotic isozymes and by bacterial AspC. PAINT places it at the eukaryotic mitochondrial-type node, the cytosolic node and a gammaproteobacterial AspC node. TyrB also transaminates aspartate, but its physiological role is aromatic; the fungal secondary-metabolism members (tasG, ucdG) were not checked. The aspartate/asparagine and malate-aspartate shuttle modules use the family id with compartment-specific representatives, which is appropriate.

Gene-review completeness (6/6 grounded genes reviewed)

6 complete review(s) · 0 with deep research · 0 missing review · 6 reviewed but lacking deep research

Gene Review Complete Deep research
GOT1 P17174 ✓ ✓ ✗
GOT2 P00505 ✓ ✓ ✗
MDH1 P40925 ✓ ✓ ✗
MDH2 P40926 ✓ ✓ ✗
SLC25A11 Q02978 ✓ ✓ ✗
SLC25A12 O75746 ✓ ✓ ✗

Details

Context
cytosolGO:0005829 mitochondrial inner membraneGO:0005743 mitochondrial matrixGO:0005759
Malate-aspartate shuttleMetabolic Pathwaymalate_aspartate_shuttle
malate-aspartate shuttleGO:0043490
Context
cytosolGO:0005829 mitochondrial inner membraneGO:0005743 mitochondrial matrixGO:0005759

The malate-aspartate shuttle (GO:0043490), grounded to the completed human gene reviews: cytosolic arm MDH1 (P40925, GO:0030060) + GOT1 (P17174, GO:0004069, PLP GO:0030170); inner-membrane carriers SLC25A11/OGC (Q02978, GO:0015367 oxoglutarate:malate antiporter) + SLC25A12/AGC1/aralar (O75746, GO:0000515 aspartate:glutamate,proton antiporter + Ca2+ binding GO:0005509); matrix arm MDH2 (P40926, GO:0030060, also TCA cycle) + GOT2 (P00505, GO:0004069, PLP; with a genuine FABPpm/ fatty-acid-uptake moonlighting role kept non-core). Net effect: a cytosolic NADH is oxidised (MDH1) and a matrix NADH regenerated (MDH2), transferring reducing equivalents inward without moving NADH across the membrane; the electrogenic, Ca2+-activated AGC1 antiport sets the direction. GO term ids/ labels verified against the local go.db. This shuttle feeds electrons to respiratory Complex I (curated in the mitochondrial_complex_i_core / assembly / accessory modules). Disorders: AGC1 (SLC25A12) deficiency — global cerebral hypomyelination/epilepsy; MDH2 and GOT2 deficiency — early infantile epileptic encephalopathy.

Connections

mas_cytosolic_arm -> mas_carriers Provides Input For
Cytosolic MDH1 supplies malate to the OGC; GOT1 consumes the aspartate delivered by AGC1.
mas_carriers -> mas_matrix_arm Provides Input For
The OGC delivers malate to matrix MDH2; AGC1 delivers glutamate to matrix GOT2.
mas_matrix_arm -> mas_carriers Provides Input For
Matrix GOT2 supplies aspartate to AGC1 and 2-oxoglutarate to the OGC, closing the cycle.
Part 1: cytosolic arm (consumes cytosolic NADH; regenerates aspartate acceptor)
Cytosolic arm (MDH1, GOT1)Reactionmas_cytosolic_arm

Annotons

MDH1: cytosolic malate dehydrogenase
mdh1_activity
Participant: Family: cytosolic malate dehydrogenase (MDH1) family
Family:
cytosolic malate dehydrogenase (MDH1) familyPANTHER:PTHR23382
Representative Members: MDH1 (human)UniProtKB:P40925

Function

L-malate dehydrogenase (NAD+) activityGO:0030060
Substrates: oxaloacetate NADH (cytosolic)
Products: (S)-malate NAD+

Locations

cytosolGO:0005829

Reduces oxaloacetate to malate, consuming a cytosolic NADH.

GOT1: cytosolic aspartate aminotransferase
got1_activity
Participant: Family: aspartate aminotransferase (GOT) family
Family:
aspartate aminotransferase (GOT) familyPANTHER:PTHR11879
Representative Members: GOT1 (human)UniProtKB:P17174

Function

L-aspartate:2-oxoglutarate transaminase activityGO:0004069
Substrates: L-aspartate (from AGC1) 2-oxoglutarate
Products: oxaloacetate L-glutamate

Locations

cytosolGO:0005829

Transaminates aspartate + 2-oxoglutarate to oxaloacetate + glutamate.

Part 2: inner-membrane carriers (malate/2-oxoglutarate and aspartate/glutamate exchange)
Inner-membrane carriers (SLC25A11 OGC, SLC25A12 AGC1)Reactionmas_carriers

Annotons

SLC25A11 (OGC): oxoglutarate/malate carrier
slc25a11_activity
Participant: Family: SLC25A11 / oxoglutarate-malate carrier family
Family:
SLC25A11 / oxoglutarate-malate carrier familyPANTHER:PTHR45618
Representative Members: SLC25A11 (human)UniProtKB:Q02978

Function

oxoglutarate:malate antiporter activityGO:0015367
Substrates: (S)-malate (cytosolic) 2-oxoglutarate (matrix)
Products: (S)-malate (matrix) 2-oxoglutarate (cytosolic)

Locations

mitochondrial inner membraneGO:0005743

Imports malate in exchange for 2-oxoglutarate.

SLC25A12 (AGC1/aralar): aspartate-glutamate carrier
slc25a12_activity
Participant: Family: SLC25A12 / aspartate-glutamate carrier (aralar) family
Family:
SLC25A12 / aspartate-glutamate carrier (aralar) familyPANTHER:PTHR45678
Representative Members: SLC25A12 (human)UniProtKB:O75746

Function

aspartate:glutamate, proton antiporter activityGO:0000515
Substrates: L-aspartate (matrix) L-glutamate (cytosolic) + H+
Products: L-aspartate (cytosolic) L-glutamate (matrix)

Locations

mitochondrial inner membraneGO:0005743

Exports aspartate in exchange for cytosolic glutamate (Ca2+-regulated, electrogenic).

Part 3: matrix arm (regenerates matrix NADH; regenerates aspartate)
Matrix arm (MDH2, GOT2)Reactionmas_matrix_arm

Annotons

MDH2: matrix malate dehydrogenase
mdh2_activity
Participant: Family: mitochondrial malate dehydrogenase (MDH2) family
Family:
mitochondrial malate dehydrogenase (MDH2) familyPANTHER:PTHR11540
Representative Members: MDH2 (human)UniProtKB:P40926

Function

L-malate dehydrogenase (NAD+) activityGO:0030060
Substrates: (S)-malate (matrix) NAD+
Products: oxaloacetate NADH (matrix; feeds Complex I)

Locations

mitochondrial matrixGO:0005759

Re-oxidises malate to oxaloacetate, regenerating matrix NADH.

GOT2: matrix aspartate aminotransferase
got2_activity
Participant: Family: aspartate aminotransferase (GOT) family
Family:
aspartate aminotransferase (GOT) familyPANTHER:PTHR11879
Representative Members: GOT2 (human)UniProtKB:P00505

Function

L-aspartate:2-oxoglutarate transaminase activityGO:0004069
Substrates: oxaloacetate L-glutamate (from AGC1)
Products: L-aspartate 2-oxoglutarate

Locations

mitochondrial matrixGO:0005759

Transaminates oxaloacetate + glutamate to aspartate + 2-oxoglutarate.