Metabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons
Abstract In Alzheimer's disease (AD), dysfunctional mitochondrial metabolism is associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, is still lacking. Here, comparing isogenic wild‐type and AD mutant human indu...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-03-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202306469 |
| _version_ | 1797242658043723776 |
|---|---|
| author | Alexander Y. Andreyev Hongmei Yang Paschalis‐Thomas Doulias Nima Dolatabadi Xu Zhang Melissa Luevanos Mayra Blanco Christine Baal Ivan Putra Tomohiro Nakamura Harry Ischiropoulos Steven R. Tannenbaum Stuart A. Lipton |
| author_facet | Alexander Y. Andreyev Hongmei Yang Paschalis‐Thomas Doulias Nima Dolatabadi Xu Zhang Melissa Luevanos Mayra Blanco Christine Baal Ivan Putra Tomohiro Nakamura Harry Ischiropoulos Steven R. Tannenbaum Stuart A. Lipton |
| author_sort | Alexander Y. Andreyev |
| collection | DOAJ |
| description | Abstract In Alzheimer's disease (AD), dysfunctional mitochondrial metabolism is associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, is still lacking. Here, comparing isogenic wild‐type and AD mutant human induced pluripotent stem cell (hiPSC)‐derived cerebrocortical neurons (hiN), evidence is found for compromised mitochondrial energy in AD using the Seahorse platform to analyze glycolysis and oxidative phosphorylation (OXPHOS). Isotope‐labeled metabolic flux experiments revealed a major block in activity in the tricarboxylic acid (TCA) cycle at the α‐ketoglutarate dehydrogenase (αKGDH)/succinyl coenzyme‐A synthetase step, metabolizing α‐ketoglutarate to succinate. Associated with this block, aberrant protein S‐nitrosylation of αKGDH subunits inhibited their enzyme function. This aberrant S‐nitrosylation is documented not only in AD‐hiN but also in postmortem human AD brains versus controls, as assessed by two separate unbiased mass spectrometry platforms using both SNOTRAP identification of S‐nitrosothiols and chemoselective‐enrichment of S‐nitrosoproteins. Treatment with dimethyl succinate, a cell‐permeable derivative of a TCA substrate downstream to the block, resulted in partial rescue of mitochondrial bioenergetic function as well as reversal of synapse loss in AD‐hiN. These findings have therapeutic implications that rescue of mitochondrial energy metabolism can ameliorate synaptic loss in hiPSC‐based models of AD. |
| first_indexed | 2024-04-24T18:42:43Z |
| format | Article |
| id | doaj.art-4b2d8ce6444d4cbcb0c378825ef1c175 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-24T18:42:43Z |
| publishDate | 2024-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-4b2d8ce6444d4cbcb0c378825ef1c1752024-03-27T09:39:53ZengWileyAdvanced Science2198-38442024-03-011112n/an/a10.1002/advs.202306469Metabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human NeuronsAlexander Y. Andreyev0Hongmei Yang1Paschalis‐Thomas Doulias2Nima Dolatabadi3Xu Zhang4Melissa Luevanos5Mayra Blanco6Christine Baal7Ivan Putra8Tomohiro Nakamura9Harry Ischiropoulos10Steven R. Tannenbaum11Stuart A. Lipton12Department of Molecular Medicine and Neurodegeneration New Medicines Center The Scripps Research Institute La Jolla CA 92037 USADepartment of Biological Engineering Massachusetts Institute of Technology Cambridge MA 02139 USAChildren's Hospital of Philadelphia Research Institute and Departments of Pediatrics and Pharmacology Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania Philadelphia PA 19104 USADepartment of Molecular Medicine and Neurodegeneration New Medicines Center The Scripps Research Institute La Jolla CA 92037 USADepartment of Molecular Medicine and Neurodegeneration New Medicines Center The Scripps Research Institute La Jolla CA 92037 USADepartment of Molecular Medicine and Neurodegeneration New Medicines Center The Scripps Research Institute La Jolla CA 92037 USADepartment of Molecular Medicine and Neurodegeneration New Medicines Center The Scripps Research Institute La Jolla CA 92037 USADepartment of Molecular Medicine and Neurodegeneration New Medicines Center The Scripps Research Institute La Jolla CA 92037 USADepartment of Molecular Medicine and Neurodegeneration New Medicines Center The Scripps Research Institute La Jolla CA 92037 USADepartment of Molecular Medicine and Neurodegeneration New Medicines Center The Scripps Research Institute La Jolla CA 92037 USAChildren's Hospital of Philadelphia Research Institute and Departments of Pediatrics and Pharmacology Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania Philadelphia PA 19104 USANortheast Asia Institute of Chinese Medicine Changchun University of Chinese Medicine Changchun 130021 ChinaDepartment of Molecular Medicine and Neurodegeneration New Medicines Center The Scripps Research Institute La Jolla CA 92037 USAAbstract In Alzheimer's disease (AD), dysfunctional mitochondrial metabolism is associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, is still lacking. Here, comparing isogenic wild‐type and AD mutant human induced pluripotent stem cell (hiPSC)‐derived cerebrocortical neurons (hiN), evidence is found for compromised mitochondrial energy in AD using the Seahorse platform to analyze glycolysis and oxidative phosphorylation (OXPHOS). Isotope‐labeled metabolic flux experiments revealed a major block in activity in the tricarboxylic acid (TCA) cycle at the α‐ketoglutarate dehydrogenase (αKGDH)/succinyl coenzyme‐A synthetase step, metabolizing α‐ketoglutarate to succinate. Associated with this block, aberrant protein S‐nitrosylation of αKGDH subunits inhibited their enzyme function. This aberrant S‐nitrosylation is documented not only in AD‐hiN but also in postmortem human AD brains versus controls, as assessed by two separate unbiased mass spectrometry platforms using both SNOTRAP identification of S‐nitrosothiols and chemoselective‐enrichment of S‐nitrosoproteins. Treatment with dimethyl succinate, a cell‐permeable derivative of a TCA substrate downstream to the block, resulted in partial rescue of mitochondrial bioenergetic function as well as reversal of synapse loss in AD‐hiN. These findings have therapeutic implications that rescue of mitochondrial energy metabolism can ameliorate synaptic loss in hiPSC‐based models of AD.https://doi.org/10.1002/advs.202306469Alzheimer's diseasesS‐nitrosylationtricarboxylic acid cycles |
| spellingShingle | Alexander Y. Andreyev Hongmei Yang Paschalis‐Thomas Doulias Nima Dolatabadi Xu Zhang Melissa Luevanos Mayra Blanco Christine Baal Ivan Putra Tomohiro Nakamura Harry Ischiropoulos Steven R. Tannenbaum Stuart A. Lipton Metabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons Advanced Science Alzheimer's diseases S‐nitrosylation tricarboxylic acid cycles |
| title | Metabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons |
| title_full | Metabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons |
| title_fullStr | Metabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons |
| title_full_unstemmed | Metabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons |
| title_short | Metabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons |
| title_sort | metabolic bypass rescues aberrant s nitrosylation induced tca cycle inhibition and synapse loss in alzheimer s disease human neurons |
| topic | Alzheimer's diseases S‐nitrosylation tricarboxylic acid cycles |
| url | https://doi.org/10.1002/advs.202306469 |
| work_keys_str_mv | AT alexanderyandreyev metabolicbypassrescuesaberrantsnitrosylationinducedtcacycleinhibitionandsynapselossinalzheimersdiseasehumanneurons AT hongmeiyang metabolicbypassrescuesaberrantsnitrosylationinducedtcacycleinhibitionandsynapselossinalzheimersdiseasehumanneurons AT paschalisthomasdoulias metabolicbypassrescuesaberrantsnitrosylationinducedtcacycleinhibitionandsynapselossinalzheimersdiseasehumanneurons AT nimadolatabadi metabolicbypassrescuesaberrantsnitrosylationinducedtcacycleinhibitionandsynapselossinalzheimersdiseasehumanneurons AT xuzhang metabolicbypassrescuesaberrantsnitrosylationinducedtcacycleinhibitionandsynapselossinalzheimersdiseasehumanneurons AT melissaluevanos metabolicbypassrescuesaberrantsnitrosylationinducedtcacycleinhibitionandsynapselossinalzheimersdiseasehumanneurons AT mayrablanco metabolicbypassrescuesaberrantsnitrosylationinducedtcacycleinhibitionandsynapselossinalzheimersdiseasehumanneurons AT christinebaal metabolicbypassrescuesaberrantsnitrosylationinducedtcacycleinhibitionandsynapselossinalzheimersdiseasehumanneurons AT ivanputra metabolicbypassrescuesaberrantsnitrosylationinducedtcacycleinhibitionandsynapselossinalzheimersdiseasehumanneurons AT tomohironakamura metabolicbypassrescuesaberrantsnitrosylationinducedtcacycleinhibitionandsynapselossinalzheimersdiseasehumanneurons AT harryischiropoulos metabolicbypassrescuesaberrantsnitrosylationinducedtcacycleinhibitionandsynapselossinalzheimersdiseasehumanneurons AT stevenrtannenbaum metabolicbypassrescuesaberrantsnitrosylationinducedtcacycleinhibitionandsynapselossinalzheimersdiseasehumanneurons AT stuartalipton metabolicbypassrescuesaberrantsnitrosylationinducedtcacycleinhibitionandsynapselossinalzheimersdiseasehumanneurons |