Inner mitochondrial membrane

evidence_span

{"source_cache": "artifacts/lutein-research/25002123.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "13eecc413b623871f99140525333718bec180923ca6673fab15a9dee19a0551b", "start_char": 0, "end_char": 1308, "text_sha256": "13eecc413b623871f99140525333718bec180923ca6673fab15a9dee19a0551b"}

experimental_model

Subcellular localization and mitochondrial fractionation

exposure

Cleavable N-terminal leaders and compartment analyses

limitations

Human cell localization and mouse organelle fractionation are separate evidence components.

nutrient_topic

Lutein research collection; topical membership is not evidence of a direct dietary effect. · Lutein

organism

Human isoforms in cell lines and mouse liver

plain_language

Carotenoid breakdown is organized within a particular compartment.

primary_references

[lutein-p25002123] Evidence for compartmentalization of mammalian carotenoid metabolism. (2014). https://pubmed.ncbi.nlm.nih.gov/25002123/ DOI: 10.1096/fj.14-252411

tissue_or_cell_type

Inner mitochondrial membrane

Lutein: metabolism, signaling and nutrient connections (2026-09-17) · lines 307–318

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Subcellular localization and mitochondrial fractionation · source_derived_draft · unverified_draft

### lutein-bco2-inner-membrane Human BCO2 associated with the inner mitochondrial membrane in cell-line experiments. Condition category: normal nutrient_topic: Lutein research collection; topical membership is not evidence of a direct dietary effect. plain_language: Carotenoid breakdown is organized within a particular compartment. organism: Human isoforms in cell lines and mouse liver tissue_or_cell_type: Inner mitochondrial membrane experimental_model: Subcellular localization and mitochondrial fractionation limitations: Human cell localization and mouse organelle fractionation are separate evidence components. exposure: Cleavable N-terminal leaders and compartment analyses evidence_span: {"source_cache": "artifacts/lutein-research/25002123.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "13eecc413b623871f99140525333718bec180923ca6673fab15a9dee19a0551b", "start_char": 0, "end_char": 1308, "text_sha256": "13eecc413b623871f99140525333718bec180923ca6673fab15a9dee19a0551b"} [lutein-p25002123] Evidence for compartmentalization of mammalian carotenoid metabolism. (2014). https://pubmed.ncbi.nlm.nih.gov/25002123/ DOI: 10.1096/fj.14-252411

experimental_model

Tagged human protein, mitochondrial fractionation

exposure

Assay conditions described in the linked primary study.

limitations

Tagging and heterologous expression may affect localization.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens protein in Cricetulus griseus cells

plain_language

The formate-pathway enzyme sits on the mitochondrial inner surface.

primary_references

[prasannan-2009] Human mitochondrial C1-tetrahydrofolate synthase: submitochondrial localization of the full-length enzyme and characterization of a short isoform (2009). https://pubmed.ncbi.nlm.nih.gov/18996079/ DOI: 10.1016/j.abb.2008.10.028

tissue_or_cell_type

CHO cells

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 875–885

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Tagged human protein, mitochondrial fractionation · source_derived_draft · unverified_draft

### mthfd1l-matrix-face Human MTHFD1L expressed in CHO cells behaves as a peripheral protein at the matrix face of the inner mitochondrial membrane. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The formate-pathway enzyme sits on the mitochondrial inner surface. organism: Homo sapiens protein in Cricetulus griseus cells tissue_or_cell_type: CHO cells experimental_model: Tagged human protein, mitochondrial fractionation limitations: Tagging and heterologous expression may affect localization. exposure: Assay conditions described in the linked primary study. [prasannan-2009] Human mitochondrial C1-tetrahydrofolate synthase: submitochondrial localization of the full-length enzyme and characterization of a short isoform (2009). https://pubmed.ncbi.nlm.nih.gov/18996079/ DOI: 10.1016/j.abb.2008.10.028

availability_state

machinery_impairment Imported condition classification; unverified.

compartment_description

Inner mitochondrial membrane

experimental_model

Cultured mammalian cells and in vivo mouse-liver MCU silencing

limitations

No inference of universal respiratory failure or dietary calcium deficiency.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens and Mus musculus

plain_language

Removing MCU prevents rapid calcium uptake without necessarily collapsing the mitochondrion.

primary_references

[ca-baughman2011] Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter (2011). https://pubmed.ncbi.nlm.nih.gov/21685886/ DOI: 10.1038/nature10234

research_relationship_category

loss_of_function

tissue_or_cell_type

Cultured cells and mouse liver

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 693–704

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured mammalian cells and in vivo mouse-liver MCU silencing · source_derived_draft · unverified_draft

### ca-mcu-loss-matrix-uptake MCU silencing sharply reduces mitochondrial calcium uptake while membrane potential and respiration remain intact in the tested preparations. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing MCU prevents rapid calcium uptake without necessarily collapsing the mitochondrion. organism: Homo sapiens and Mus musculus tissue_or_cell_type: Cultured cells and mouse liver experimental_model: Cultured mammalian cells and in vivo mouse-liver MCU silencing limitations: No inference of universal respiratory failure or dietary calcium deficiency. research_relationship_category: loss_of_function compartment_description: Inner mitochondrial membrane [ca-baughman2011] Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter (2011). https://pubmed.ncbi.nlm.nih.gov/21685886/ DOI: 10.1038/nature10234

compartment_description

Inner mitochondrial membrane

experimental_model

Human HeLa MCU silencing/overexpression and purified MCU in planar bilayers

limitations

Pore and overexpression evidence; native uptake also depends on accessory subunits and membrane potential.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

MCU lets calcium enter the mitochondrial matrix.

primary_references

[ca-destefani2011] A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter (2011). https://pubmed.ncbi.nlm.nih.gov/21685888/ DOI: 10.1038/nature10230

research_relationship_category

transport

tissue_or_cell_type

HeLa cells and purified channel

transport_effect

raises Recorded as promoting agonist-evoked matrix calcium uptake.

transport_or_reaction_direction

Intermembrane space to mitochondrial matrix

transport_pool

mitochondrial matrix calcium Recorded as promoting agonist-evoked matrix calcium uptake.

Calcium: mechanism-first literature curation (2026-09-17) · lines 679–691

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HeLa MCU silencing/overexpression and purified MCU in planar bilayers · source_derived_draft · unverified_draft

### ca-mcu-matrix-uptake MCU supplies the inner-mitochondrial-membrane calcium-conducting pore and promotes agonist-evoked matrix calcium uptake. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: MCU lets calcium enter the mitochondrial matrix. organism: Homo sapiens tissue_or_cell_type: HeLa cells and purified channel experimental_model: Human HeLa MCU silencing/overexpression and purified MCU in planar bilayers limitations: Pore and overexpression evidence; native uptake also depends on accessory subunits and membrane potential. research_relationship_category: transport transport_or_reaction_direction: Intermembrane space to mitochondrial matrix compartment_description: Inner mitochondrial membrane [ca-destefani2011] A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter (2011). https://pubmed.ncbi.nlm.nih.gov/21685888/ DOI: 10.1038/nature10230

compartment_description

Inner mitochondrial membrane

experimental_model

Isolated mammalian mitochondria and mitoplast macroscopic/single-channel patch clamp

limitations

Contested interpretation; mitoplast preparation and subunit abundance are challenged by Tsai 2023. Not a settled universal edge.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mammalia

plain_language

One electrophysiological study proposes that MICU proteins increase channel opening during calcium signals.

primary_references

[ca-garg2021] The mechanism of MICU-dependent gating of the mitochondrial Ca2+ uniporter (2021). https://pubmed.ncbi.nlm.nih.gov/34463251/ DOI: 10.7554/eLife.69312

tissue_or_cell_type

Isolated mitochondria and mitoplasts

Calcium: mechanism-first literature curation (2026-09-17) · lines 745–755

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated mammalian mitochondria and mitoplast macroscopic/single-channel patch clamp · source_derived_draft · unverified_draft

### ca-micu-potentiation-model Garg and colleagues interpret mitochondrial currents as MICU-dependent enhancement of uniporter opening at elevated external calcium, without pore occlusion. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: One electrophysiological study proposes that MICU proteins increase channel opening during calcium signals. organism: Mammalia tissue_or_cell_type: Isolated mitochondria and mitoplasts experimental_model: Isolated mammalian mitochondria and mitoplast macroscopic/single-channel patch clamp limitations: Contested interpretation; mitoplast preparation and subunit abundance are challenged by Tsai 2023. Not a settled universal edge. compartment_description: Inner mitochondrial membrane [ca-garg2021] The mechanism of MICU-dependent gating of the mitochondrial Ca2+ uniporter (2021). https://pubmed.ncbi.nlm.nih.gov/34463251/ DOI: 10.7554/eLife.69312

compartment_description

Mitochondrial uniporter regulatory machinery

experimental_model

HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays

limitations

Threshold and molecular explanation are assay-dependent; see the separate MICU1 gating conflict.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

MICU1 helps prevent unnecessary calcium accumulation in resting mitochondria.

primary_references

[ca-mallilankaraman2012] MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival (2012). https://pubmed.ncbi.nlm.nih.gov/23101630/ DOI: 10.1016/j.cell.2012.10.011

research_relationship_category

regulation

tissue_or_cell_type

HeLa, HEK293 and endothelial cells

Calcium: mechanism-first literature curation (2026-09-17) · lines 706–717

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays · source_derived_draft · unverified_draft

### ca-micu1-basal-uptake-restraint MICU1 limits MCU-dependent calcium uptake at low external calcium in the examined cell preparations. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: MICU1 helps prevent unnecessary calcium accumulation in resting mitochondria. organism: Homo sapiens tissue_or_cell_type: HeLa, HEK293 and endothelial cells experimental_model: HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays limitations: Threshold and molecular explanation are assay-dependent; see the separate MICU1 gating conflict. research_relationship_category: regulation compartment_description: Mitochondrial uniporter regulatory machinery [ca-mallilankaraman2012] MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival (2012). https://pubmed.ncbi.nlm.nih.gov/23101630/ DOI: 10.1016/j.cell.2012.10.011

compartment_description

Intermembrane-space face of inner mitochondrial membrane

experimental_model

Purified MICU1 addition, mitoplast patch clamp and intact mitochondrial ion-flux assays

limitations

Supports pore occlusion in these assays; competing potentiation evidence remains linked rather than discarded.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mammalia

plain_language

A later study directly observes MICU1 inhibiting the uniporter.

primary_references

[ca-tsai2023] Evidence supporting the MICU1 occlusion mechanism and against the potentiation model in the mitochondrial calcium uniporter complex (2023). https://pubmed.ncbi.nlm.nih.gov/37036971/ DOI: 10.1073/pnas.2217665120

research_relationship_category

mechanistic_evidence

tissue_or_cell_type

Reconstituted protein and mitochondrial preparations

Calcium: mechanism-first literature curation (2026-09-17) · lines 757–768

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified MICU1 addition, mitoplast patch clamp and intact mitochondrial ion-flux assays · source_derived_draft · unverified_draft

### ca-micu1-occlusion-evidence Purified MICU1 suppresses MCU-complex currents in patch-clamp experiments, and disruption of its MCU-interacting K126 residue abolishes this suppression. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A later study directly observes MICU1 inhibiting the uniporter. organism: Mammalia tissue_or_cell_type: Reconstituted protein and mitochondrial preparations experimental_model: Purified MICU1 addition, mitoplast patch clamp and intact mitochondrial ion-flux assays limitations: Supports pore occlusion in these assays; competing potentiation evidence remains linked rather than discarded. research_relationship_category: mechanistic_evidence compartment_description: Intermembrane-space face of inner mitochondrial membrane [ca-tsai2023] Evidence supporting the MICU1 occlusion mechanism and against the potentiation model in the mitochondrial calcium uniporter complex (2023). https://pubmed.ncbi.nlm.nih.gov/37036971/ DOI: 10.1073/pnas.2217665120

compartment_description

Inner mitochondrial membrane and matrix

experimental_model

Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts

limitations

Experimental overload; not all apoptosis uses this pathway and the study does not settle the molecular identity of the pore.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

Excess mitochondrial calcium can trigger membrane permeability failure.

primary_references

[ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434

research_relationship_category

exposure_response

tissue_or_cell_type

Isolated liver, heart and brain mitochondria

Calcium: mechanism-first literature curation (2026-09-17) · lines 836–847

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts · source_derived_draft · unverified_draft

### ca-overload-permeability-transition Calcium-overload conditions induce cyclophilin-D-sensitive mitochondrial permeability transition and swelling in the tested mouse preparations. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Excess mitochondrial calcium can trigger membrane permeability failure. organism: Mus musculus tissue_or_cell_type: Isolated liver, heart and brain mitochondria experimental_model: Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts limitations: Experimental overload; not all apoptosis uses this pathway and the study does not settle the molecular identity of the pore. research_relationship_category: exposure_response compartment_description: Inner mitochondrial membrane and matrix [ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/nnt-structure-2019.abstract.txt", "locator": "Indexed abstract, reaction and structural mechanism", "start_char": 199, "end_char": 1759, "file_sha256": "edb35c2cdf2f57d604cb86da48665e5742d398f43c50f3e1622d161564c78a83", "text_sha256": "aa5063e57c35097c2fa2557ed9a7d61c3a411d90d0ded9b947525012520a5712"}

experimental_model

Cryo-EM of intact ovine NNT in different nucleotide states

exposure

Nucleotide-bound conformational states

limitations

Structural mechanism supported in ovine protein; forward flux is context dependent and not equivalent to adding phosphate to NAD. No human intake inference.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Ovis aries

plain_language

NNT links the NADH and NADPH redox systems through membrane-coupled chemistry.

primary_references

[nnt-structure-2019] Structure and mechanism of mitochondrial proton-translocating transhydrogenase. (2019). https://pubmed.ncbi.nlm.nih.gov/31462775/ DOI: 10.1038/s41586-019-1519-2

tissue_or_cell_type

Purified mitochondrial protein

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1003–1014

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cryo-EM of intact ovine NNT in different nucleotide states · source_derived_draft · unverified_draft

### b3-redox-nnt-coupling Structural analysis of mammalian NNT supported coupling of NADH-to-NADP+ hydride transfer to proton translocation across the mitochondrial membrane. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: NNT links the NADH and NADPH redox systems through membrane-coupled chemistry. organism: Ovis aries tissue_or_cell_type: Purified mitochondrial protein experimental_model: Cryo-EM of intact ovine NNT in different nucleotide states limitations: Structural mechanism supported in ovine protein; forward flux is context dependent and not equivalent to adding phosphate to NAD. No human intake inference. exposure: Nucleotide-bound conformational states evidence_span: {"source_cache": "artifacts/niacin-redox-sources/nnt-structure-2019.abstract.txt", "locator": "Indexed abstract, reaction and structural mechanism", "start_char": 199, "end_char": 1759, "file_sha256": "edb35c2cdf2f57d604cb86da48665e5742d398f43c50f3e1622d161564c78a83", "text_sha256": "aa5063e57c35097c2fa2557ed9a7d61c3a411d90d0ded9b947525012520a5712"} [nnt-structure-2019] Structure and mechanism of mitochondrial proton-translocating transhydrogenase. (2019). https://pubmed.ncbi.nlm.nih.gov/31462775/ DOI: 10.1038/s41586-019-1519-2

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 18765, "end_char": 19491, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "151d453cb71149ec656b6e82375a1e679d977643e107133d197cac4a5df0f7b9"}

experimental_model

HEK293T knockdown and HAP1 knockout mitochondria with genetic rescue

exposure

1 mM exogenous NAD+; 40-min uptake incubation

limitations

Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

The transporter restored mitochondrial entry of intact NAD+.

primary_references

[slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7

tissue_or_cell_type

Isolated mitochondria

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1029–1040

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HEK293T knockdown and HAP1 knockout mitochondria with genetic rescue · source_derived_draft · unverified_draft

### b3-redox-slc25a51-import Re-expression of SLC25A51 restored exogenous NAD+ uptake into mitochondria isolated from SLC25A51-deficient cells. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The transporter restored mitochondrial entry of intact NAD+. organism: Homo sapiens tissue_or_cell_type: Isolated mitochondria experimental_model: HEK293T knockdown and HAP1 knockout mitochondria with genetic rescue limitations: Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested. exposure: 1 mM exogenous NAD+; 40-min uptake incubation evidence_span: {"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 18765, "end_char": 19491, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "151d453cb71149ec656b6e82375a1e679d977643e107133d197cac4a5df0f7b9"} [slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7