Johanne Egge Rinholm

• Lier, Silje; Markusson, Sara Bachmann; Kocijančič, Anja; Narum, Martine; Lund, Solveig Osnes & Böllering, Bianka [Vis alle 30 forfattere av denne artikkelen] (2026). CDK12/CDK13 inhibition disrupts transcriptional elongation and replication fork progression in glioblastoma. EMBO Molecular Medicine. ISSN 1757-4676. 18, s. 1592–1624. doi: 10.1038/s44321-026-00393-w. Fulltekst i vitenarkiv Vis sammendrag

  Glioblastomas are the most prevalent and aggressive malignant brain tumors, characterized by hypertranscription and dependence on neurodevelopmental transcription factors. The transcriptional cycle is regulated by phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (RNAPII) by transcriptional cyclin-dependent kinases (tCDKs), including CDK7, CDK9, CDK12, and CDK13. Here we find that glioblastoma stem cells (GSCs) are selectively sensitive to CDK12/CDK13 inhibition, whereas CDK7 and CDK9 inhibition cause non-specific cytotoxicity. This selective targeting halts GSC and organoid proliferation, curtails GSC invasion and suppresses tumor growth in a xenograft mouse model. In GSCs, CDK12/CDK13 inhibition leads to a rapid and genome-wide loss of serine-2 phosphorylation (pSer2) of the RNAPII CTD, abolishing transcriptional elongation and a transcriptional program sustained by key neurodevelopmental transcription factors. CDK12/CDK13 inhibition unexpectedly arrests DNA replication and replication fork progression in a manner distinct from the effect of inhibiting other tCDKs. This dramatic arrest precedes DNA damage response activation and cell cycle arrest, directly linking RNAPII elongation to replication fork dynamics and revealing a previously unrecognized dependence of DNA replication on CDK12/CDK13-RNAPII regulation.

• Kennedy, Lauritz Hagen; Morland, Cecilie; Narum, Martine; Bergersen, Linda Hildegard & Rinholm, Johanne Egge (2025). Lactate Receptor HCAR1 Affects Axonal Development and Contributes to Lactate’s Protection of Axons and Myelin in Experimental Neonatal Hypoglycemia. eNeuro. 12(5). doi: 10.1523/eneuro.0563-24.2025. Fulltekst i vitenarkiv Vis sammendrag

  Lactate plays an important role in brain energy metabolism. It contributes to normal brain development and to neuroprotection in diabetic hypoglycemia, but its role in neonatal hypoglycemia is unclear. Moreover, lactate can work as a signaling substance via the lactate receptor HCAR1 (Hydroxycarboxylic acid receptor 1). Recent studies indicate that HCAR1 is protective in mouse models of neonatal hypoxic ischemia and has a role in metabolic regulation in glial cells during hypoglycemia. Here we have studied potential impacts of HCAR1 on axonal and myelin development in the cerebral cortex and corpus callosum of young (P21) wild-type (WT) mice and HCAR1 KO mice and in cortical organotypic brain slice cultures. The HCAR1 KO mice showed lower axonal area relative to WT in both cortex and corpus callosum. However, the myelin area was unaffected by HCAR1 KO. Using particle and colocalization analysis, we show that HCAR1 KO predominantly reduces axonal size in unmyelinated axons. Using an organotypic brain slice model of neonatal hypoglycemia, we find that lactate protects both axonal and myelin development in hypoglycemia, partially via HCAR1. Lastly, live imaging with a pH-sensitive dye on acute cortical brain slices indicates that cellular lactate uptake is influenced by HCAR1. In conclusion, our findings support a role of HCAR1 in axonal development and in lactate’s protective effects in hypoglycemia.

• Lin, Xiaolin; Wang, Wei; Yang, Mingyi; Damseh, Nadirah; Sousa, Mirta & Jacob, Fadi [Vis alle 29 forfattere av denne artikkelen] (2023). A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatial–temporal regulation of histone arginine methylation in neurodevelopment. Genome Biology. ISSN 1465-6906. 24(1). doi: 10.1186/s13059-023-03037-1. Fulltekst i vitenarkiv Vis sammendrag

  Background Oxidation Resistance 1 (OXR1) gene is a highly conserved gene of the TLDc domain-containing family. OXR1 is involved in fundamental biological and cellular processes, including DNA damage response, antioxidant pathways, cell cycle, neuronal protection, and arginine methylation. In 2019, five patients from three families carrying four biallelic loss-of-function variants in OXR1 were reported to be associated with cerebellar atrophy. However, the impact of OXR1 on cellular functions and molecular mechanisms in the human brain is largely unknown. Notably, no human disease models are available to explore the pathological impact of OXR1 deficiency. Results We report a novel loss-of-function mutation in the TLDc domain of the human OXR1 gene, resulting in early-onset epilepsy, developmental delay, cognitive disabilities, and cerebellar atrophy. Patient lymphoblasts show impaired cell survival, proliferation, and hypersensitivity to oxidative stress. These phenotypes are rescued by TLDc domain replacement. We generate patient-derived induced pluripotent stem cells (iPSCs) revealing impaired neural differentiation along with dysregulation of genes essential for neurodevelopment. We identify that OXR1 influences histone arginine methylation by activating protein arginine methyltransferases (PRMTs), suggesting OXR1-dependent mechanisms regulating gene expression during neurodevelopment. We model the function of OXR1 in early human brain development using patient-derived brain organoids revealing that OXR1 contributes to the spatial–temporal regulation of histone arginine methylation in specific brain regions. Conclusions This study provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency in patients.

• Kennedy, Lauritz Hagen; Glesaaen, Emilie Rylund; Palibrk, Vuk; Pannone, Marco; Wang, Wei & Al-Jabri, Ali [Vis alle 13 forfattere av denne artikkelen] (2022). Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia. eLIFE. 11. doi: 10.7554/eLife.76451. Fulltekst i vitenarkiv Vis sammendrag

  Neonatal cerebral hypoxia-ischemia (HI) is the leading cause of death and disability in newborns with the only current treatment being hypothermia. An increased understanding of the pathways that facilitate tissue repair after HI may aid the development of better treatments. Here, we study the role of lactate receptor HCAR1 in tissue repair after neonatal HI in mice. We show that HCAR1 knockout mice have reduced tissue regeneration compared with wildtype mice. Furthermore, proliferation of neural progenitor cells and glial cells, as well as microglial activation was impaired. Transcriptome analysis showed a strong transcriptional response to HI in the subventricular zone of wildtype mice involving about 7300 genes. In contrast, the HCAR1 knockout mice showed a modest response, involving about 750 genes. Notably, fundamental processes in tissue repair such as cell cycle and innate immunity were dysregulated in HCAR1 knockout. Our data suggest that HCAR1 is a key transcriptional regulator of pathways that promote tissue regeneration after HI.

• Lauritzen, Knut H.; Olsen, Maria Belland; Ahmed, Mohammed Shakil; Yang, Kuan; Rinholm, Johanne Egge & Bergersen, Linda H. [Vis alle 13 forfattere av denne artikkelen] (2021). Instability in nad+ metabolism leads to impaired cardiac mitochondrial function and communication. eLIFE. 10, s. 1–23. doi: 10.7554/ELIFE.59828. Fulltekst i vitenarkiv Vis sammendrag

  Poly(ADP-ribose) polymerase (PARP) enzymes initiate (mt)DNA repair mechanisms and use nicotinamide adenine dinucleotide (NAD+) as energy source. Prolonged PARP activity can drain cellular NAD+ reserves, leading to de-regulation of important molecular processes. Here, we provide evidence of a pathophysiological mechanism that connects mtDNA damage to cardiac dysfunction via reduced NAD+ levels and loss of mitochondrial function and communication. Using a transgenic model, we demonstrate that high levels of mice cardiomyocyte mtDNA damage cause a reduction in NAD+ levels due to extreme DNA repair activity, causing impaired activation of NAD+-dependent SIRT3. In addition, we show that myocardial mtDNA damage in combination with high dosages of nicotinamideriboside (NR) causes an inhibition of sirtuin activity due to accumulation of nicotinamide (NAM), in addition to irregular cardiac mitochondrial morphology. Consequently, high doses of NR should be used with caution, especially when cardiomyopathic symptoms are caused by mitochondrial dysfunction and instability of mtDNA.

• Meyer, Niklas & Rinholm, Johanne Egge (2021). Mitochondria in myelinating oligodendrocytes: Slow and out of breath? Metabolites. 11(6). doi: 10.3390/metabo11060359. Fulltekst i vitenarkiv Vis sammendrag

  Myelin is a lipid-rich membrane that wraps around axons and facilitates rapid action potential propagation. In the brain, myelin is synthesized and maintained by oligodendrocytes. These cells have a high metabolic demand that requires mitochondrial ATP production during the process of myelination, but they rely less on mitochondrial respiration after myelination is complete. Mitochondria change in morphology and distribution during oligodendrocyte development. Furthermore, the morphology and dynamic properties of mitochondria in mature oligodendrocytes seem different from any other brain cell. Here, we first give a brief introduction to oligodendrocyte biology and function. We then review the current knowledge on oligodendrocyte metabolism and discuss how the available data on mitochondrial morphology and mobility as well as transcriptome and proteome studies can shed light on the metabolic properties of oligodendrocytes.

• Yang, Mingyi; Lin, Xiaolin; Segers, Filip; Suganthan, Rajikala; Hildrestrand, Gunn Annette & Rinholm, Johanne Egge [Vis alle 21 forfattere av denne artikkelen] (2020). OXR1A, a Coactivator of PRMT5 Regulating Histone Arginine Methylation. Cell reports. 30(12), s. 4165–4178. doi: 10.1016/j.celrep.2020.02.063. Fulltekst i vitenarkiv Vis sammendrag

  Oxidation resistance gene 1 (OXR1) protects cells against oxidative stress. We find that male mice with brain-specific isoform A knockout (Oxr1A−/−) develop fatty liver. RNA sequencing of male Oxr1A−/− liver indicates decreased growth hormone (GH) signaling, which is known to affect liver metabolism. Indeed, Gh expression is reduced in male mice Oxr1A−/− pituitary gland and in rat Oxr1A−/− pituitary adenoma cell-line GH3. Oxr1A−/− male mice show reduced fasting-blood GH levels. Pull-down and proximity ligation assays reveal that OXR1A is associated with arginine methyl transferase PRMT5. OXR1A-depleted GH3 cells show reduced symmetrical dimethylation of histone H3 arginine 2 (H3R2me2s), a product of PRMT5 catalyzed methylation, and chromatin immunoprecipitation (ChIP) of H3R2me2s shows reduced Gh promoter enrichment. Finally, we demonstrate with purified proteins that OXR1A stimulates PRMT5/MEP50-catalyzed H3R2me2s. Our data suggest that OXR1A is a coactivator of PRMT5, regulating histone arginine methylation and thereby GH production within the pituitary gland.

• Morland, Cecilie; Andersson, Krister; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas [Vis alle 21 forfattere av denne artikkelen] (2017). Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nature Communications. 8. doi: 10.1038/ncomms15557. Fulltekst i vitenarkiv Vis sammendrag

  Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor. Editorial summary: Physical exercise promotes brain angiogenesis through an unknown signalling cascade. Morland et al. identify the elusive muscle-brain communication and show that lactate produced by muscle activity binds to its receptor HCAR1 in brain vessel-surrounding cells, stimulating VEGF production and brain angiogenesis.

• Kennedy, Lauritz Hagen & Rinholm, Johanne Egge (2017). Visualization and live imaging of oligodendrocyte organelles in organotypic brain slices using adeno-associated virus and confocal microscopy. Journal of Visualized Experiments. doi: 10.3791/56237. Fulltekst i vitenarkiv
• Rinholm, Johanne Egge; Vervaeke, Koen Gerard Alois; Tadross, Michael; Tkachuk, Ariana; Kopek, Benjamin & Brown, Timothy A [Vis alle 8 forfattere av denne artikkelen] (2016). Movement and structure of mitochondria in oligodendrocytes and their myelin sheaths. Glia. ISSN 0894-1491. 64(5), s. 810–825. doi: 10.1002/glia.22965. Fulltekst i vitenarkiv Vis sammendrag

  Mitochondria play several crucial roles in the life of oligodendrocytes. During development of the myelin sheath they are essential providers of carbon skeletons and energy for lipid synthesis. During normal brain function their consumption of pyruvate will be a key determinant of how much lactate is available for oligodendrocytes to export to power axonal function. Finally, during calcium-overload induced pathology, as occurs in ischemia, mitochondria may buffer calcium or induce apoptosis. Despite their important functions, very little is known of the properties of oligodendrocyte mitochondria, and mitochondria have never been observed in the myelin sheaths. We have now used targeted expression of fluorescent mitochondrial markers to characterize the location and movement of mitochondria within oligodendrocytes. We show for the first time that mitochondria are able to enter and move within the myelin sheath. Within the myelin sheath the highest number of mitochondria was in the cytoplasmic ridges along the sheath. Mitochondria moved more slowly than in neurons and, in contrast to their behavior in neurons and astrocytes, their movement was increased rather than inhibited by glutamate activating NMDA receptors. By electron microscopy we show that myelin sheath mitochondria have a low surface area of cristae, which suggests a low ATP production. These data specify fundamental properties of the oxidative phosphorylation system in oligodendrocytes, the glial cells that enhance cognition by speeding action potential propagation and provide metabolic support to axons.

• Rinholm, Johanne Egge & Bergersen, Linda Hildegard (2014). White matter lactate - Does it matter? Neuroscience. ISSN 0306-4522. 276, s. 109–116. doi: 10.1016/j.neuroscience.2013.10.002. Fulltekst i vitenarkiv
• Ersland, Kari Merete; Håvik, Bjarte; Rinholm, Johanne Egge; Gundersen, Vidar; Stansberg, Christine & Steen, Vidar Martin (2013). LOC689986, a unique gene showing specific expression in restricted areas of the rodent neocortex. BMC Neuroscience. 14. doi: 10.1186/1471-2202-14-68. Fulltekst i vitenarkiv Vis sammendrag

  Background: The neocortex is a highly specialised and complex brain structure, involved in numerous tasks, ranging from processing and interpretation of somatosensory information, to control of motor functions. The normal function linked to distinct neocortical areas might involve control of highly specific gene expression, and in order to identify such regionally enriched genes, we previously analysed the global gene expression in three different cortical regions (frontomedial, temporal and occipital cortex) from the adult rat brain. We identified distinct sets of differentially expressed genes. One of these genes, namely the hypothetical protein LOC689986 (LOC689986), was of particular interest, due to an almost exclusive expression in the temporal cortex. Results: Detailed analysis of LOC689986 in the adult rat brain confirmed the expression in confined areas of parieto-temporal cortex, and revealed highly specific expression in layer 4 of the somatosensory cortex, with sharp borders towards the neighbouring motor cortex. In addition, LOC689986 was found to be translated in vivo, and was detected in the somatosensory cortex and in the Purkinje cells of the cerebellar cortex. The protein was present in neuronal dendrites and also in astrocyte cells. Finally, this unique gene is apparently specific for, and highly conserved in, the vertebrate lineage. Conclusions: In this study, we have partially characterised the highly conserved LOC689986 gene, which is specific to the vertebrate linage. The gene displays a distinct pattern of expression in layer 4 of the somatosensory cortex, and areas of the parieto-temporal cortex in rodents.

• Nordengen, Kaja; Heuser, Christoph; Rinholm, Johanne Egge; Matalon, Reuben & Gundersen, Vidar (2013). Localisation of N-acetylaspartate in oligodendrocytes/myelin. Brain Structure and Function. ISSN 1863-2653. doi: 10.1007/s00429-013-0691-7. Fulltekst i vitenarkiv
• Medin, Tirill; Rinholm, Johanne Egge; Owe, Simen Gylterud; Sagvolden, Terje; Gjedde, A. & Storm-Mathisen, Jon [Vis alle 7 forfattere av denne artikkelen] (2013). LOW DOPAMINE D5 RECEPTOR DENSITY IN HIPPOCAMPUS IN AN ANIMAL MODEL OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). Neuroscience. ISSN 0306-4522. 242, s. 11–20. doi: 10.1016/j.neuroscience.2013.03.036. Fulltekst i vitenarkiv
• Bergersen, Linda Hildegard; Morland, Cecilie; Ormel, Lasse; Rinholm, Johanne Egge; Larsson, Max David & Wold, Johan Fredrik Hustad [Vis alle 13 forfattere av denne artikkelen] (2012). Immunogold Detection of L-glutamate and D-serine in Small Synaptic-Like Microvesicles in Adult Hippocampal Astrocytes. Cerebral Cortex. ISSN 1047-3211. 22(7), s. 1690–1697. doi: 10.1093/cercor/bhr254. Fulltekst i vitenarkiv
• Medin, Tirill; Owe, Simen Gylterud; Rinholm, Johanne Egge; Larsson, Max; Sagvolden, Terje & Storm-Mathisen, Jon [Vis alle 7 forfattere av denne artikkelen] (2011). Dopamine D5 receptors are localized at asymmetric synapses in the rat hippocampus. Neuroscience. ISSN 0306-4522. 192, s. 164–171. doi: 10.1016/j.neuroscience.2011.06.056. Fulltekst i vitenarkiv
• Rinholm, Johanne Egge; Hamilton, Nicola; Kessaris, Nicoletta; Richardson, William D.; Bergersen, Linda Hildegard & Attwell, David (2011). Regulation of Oligodendrocyte Development and Myelination by Glucose and Lactate. Journal of Neuroscience. ISSN 0270-6474. 31(2), s. 538–548. doi: 10.1523/JNEUROSCI.3516-10.2011. Fulltekst i vitenarkiv
• MacAskill, Andrew F.; Rinholm, Johanne Egge; Twelvetrees, Alison E.; Arancibia-Carcamo, I. Lorena; Muir, James & Fransson, Asa [Vis alle 9 forfattere av denne artikkelen] (2009). Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. Neuron. ISSN 0896-6273. 61(4), s. 541–555. Fulltekst i vitenarkiv Vis sammendrag

  Energy use, mainly to reverse ion movements in neurons, is a fundamental constraint on brain information processing. Trafficking of mitochondria to locations in neurons where there are large ion fluxes is essential for powering neural function. Mitochondrial trafficking is regulated by Ca2+ entry through ionotropic glutamate receptors, but the underlying mechanism is unknown. We show that the protein Miro1 links mitochondria to KIF5 motor proteins, allowing mitochondria to move along microtubules. This linkage is inhibited by micromolar levels of Ca2+ binding to Miro1. With the EF hand domains of Miro1 mutated to prevent Ca2+ binding, Miro1 could still facilitate mitochondrial motility, but mitochondrial stopping induced by glutamate or neuronal activity was blocked. Activating neuronal NMDA receptors with exogenous or synaptically released glutamate led to Miro1 positioning mitochondria at the postsynaptic side of synapses. Thus, Miro1 is a key determinant of how energy supply is matched to energy usage in neurons.

• Jensen, Vidar; Rinholm, Johanne Egge; Johansen, Tine Jeanette; Medin, Tirill; Storm-Mathisen, Jon & Sagvolden, Terje [Vis alle 8 forfattere av denne artikkelen] (2009). N-methyl-d-aspartate receptor subunit dysfunction at hippocampal glutamatergic synapses in an animal model of attention-deficit/hyperactivity disorder. Neuroscience. ISSN 0306-4522. 158(1), s. 353–364. doi: 10.1016/j.neuroscience.2008.05.016. Fulltekst i vitenarkiv Vis sammendrag

  Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioural disorder among children. ADHD children are hyperactive, impulsive and have problems with sustained attention. These cardinal features are also present in the best validated animal model of ADHD, the spontaneously hypertensive rat (SHR), which is derived from the Wistar Kyoto rat (WKY). Current theories of ADHD relate symptom development to factors that alter learning. N-methyl-d-aspartate receptor (NMDAR) dependent long term changes in synaptic efficacy in the mammalian CNS are thought to represent underlying cellular mechanisms for some forms of learning. We therefore hypothesized that synaptic abnormality in excitatory, glutamatergic synaptic transmission might contribute to the altered behavior in SHRs. We studied physiological and anatomical aspects of hippocampal CA3-to-CA1 synapses in age-matched SHR and WKY (controls). Electrophysiological analysis of these synapses showed reduced synaptic transmission (reduced field excitatory postsynaptic potential for a defined fiber volley size) in SHR, whereas short-term forms of synaptic plasticity, like paired-pulse facilitation, frequency facilitation, and delayed response enhancement were comparable in the two genotypes, and long-term potentiation (LTP) of synaptic transmission was of similar magnitude. However, LTP in SHR was significantly reduced (by 50%) by the NR2B specific blocker CP-101,606 (10 muM), whereas the blocker had no effect on LTP magnitude in the control rats. This indicates that the SHR has a functional predominance of NR2B, a feature characteristic of early developmental stages in these synapses. Quantitative immunofluorescence and electron microscopic postembedding immunogold cytochemistry of the three major NMDAR subunits (NR1, NR2A; and NR2B) in stratum radiatum spine synapses revealed no differences between SHR and WKY. The results indicate that functional impairments in glutamatergic synaptic transmission may be one of the underlying mechanisms leading to the abnormal behavior in SHR, and possibly in human ADHD

• Rinholm, Johanne Egge; Slettaløkken, Gunnar; Marcaggi, Paikan; Skare, Øivind; Storm-Mathisen, Jon & Bergersen, Linda Hildegard (2007). Subcellular localization of the glutamate transporters GLAST and GLT at the neuromuscular junction in rodents. Neuroscience. ISSN 0306-4522. 145. doi: 10.1016/j.neuroscience.2006.12.041. Fulltekst i vitenarkiv

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• Andersson, Krister; Morland, Cecilie; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas [Vis alle 21 forfattere av denne artikkelen] (2017). Exercise benefits brain through the lactate receptor HCAR1, increasing VEGF and capillary density in hippocampus and cortex. Fulltekst i vitenarkiv Vis sammendrag

  While physical exercise is known to improve brain function and delay neurodegeneration, the signal from muscle to brain has not been identified. We show here that the lactate receptor, hydroxycarboxylic acid receptor 1 (HCAR1 also known as GPR81), mediates exercise induced increase in the content of vascular endothelial growth factor A (VEGFA) and in capillary density in the hippocampus and cerebral cortex. Mice were subjected to high intensity interval exercise 5 days per week for 7 weeks. Increases in VEGFA and capillary density were observed in wild-type (wt) mice, but not in knockout (ko) mice lacking HCAR1. Subcutaneous injections of L-lactate 5 days per week for 7 weeks, to achieve intermittently high blood lactate levels comparable to those after exercise, reproduced the findings in wt mice. No changes were observed in ko mice. The intermittent nature of the stimulation may be important since continuously high extracellular lactate has previously been observed to down-regulate HCAR1. To our knowledge, the present finding is the first demonstration that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor. No changes in VEGFA or capillary density were observed in the cerebellar cortex. HCAR1 was highly expressed in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in fibroblast-/pericyte-like cells along intracerebral microvessels. These cells are strategically placed to monitor changes in blood-born lactate as well as in brain extracellular lactate (which equilibrate across the vascular endothelium via monocarboxylate transporter 1). Skeletal muscle showed no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. As VEGFA governs neuronal functions such as LTP as well as vascular growth, the increases may have direct effects on neurons as well as indirect effects through enhancement of vascularization. Both disturbed vascularization and impaired synaptic function are components of the pathogenesis in neurodegenerative dementias such as Alzheimer’s disease. The lactate receptor HCAR1 may prove a useful nutraceutical target for intervention in persons at risk for dementia who are unable to exercise sufficiently to achieve optimal HCAR1 stimulation through rises in blood lactate.

• Morland, Cecilie; Andersson, Krister; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas [Vis alle 18 forfattere av denne artikkelen] (2016). A novel mechanism for cerebral angiogenesis via lactate receptor HCAR1 at pial vessels. Fulltekst i vitenarkiv
• Morland, Cecilie; Andersson, Krister; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas [Vis alle 18 forfattere av denne artikkelen] (2016). Exercise induces cerebral angiogenesis via lactate receptor HCAR1 at pial vessels. Fulltekst i vitenarkiv
• Rinholm, Johanne Egge & Bergersen, Linda Hildegard (2012). The wrap that feeds neurons. Nature. ISSN 0028-0836. 487(7408), s. 435–436. doi: 10.1038/487435a. Fulltekst i vitenarkiv
• Rinholm, Johanne Egge; Hamilton, NB; Ianarelli, P; Kessaris, N; Richardson, WD & Bergersen, Linda Hildegard [Vis alle 7 forfattere av denne artikkelen] (2009). LACTATE TRANSPORTERS IN DEVELOPING OLIGODENDROCYTES. Glia. ISSN 0894-1491. 57(13), s. S113–S113. Fulltekst i vitenarkiv
• Nordhei, Astrid Fanny; Rinholm, Johanne Egge & Carlsen, Harald (2023). The role of lactate and HCAR1 in mitochondrial dynamics and neuronal survival after neonatal hypoxia-ischemia. Norges miljø- og biovitenskapelige universitet (NMBU). Fulltekst i vitenarkiv Vis sammendrag

  Neonatal Hypoxia-Ischemia (HI) is one of the most common causes for death and disabilities in infants. It is responsible for 23% of infant mortality and it affects 0.7-1.2 million neonates annually. Today the only treatment currently available is hypothermia. However, this treatment does not prevent all brain injury and many patients surviving HI develop neurological disorders such as seizures, hearing and vision loss in later years. Hence, further research is needed to develop new and effective treatments to reduce post-ischemic injury and to improve brain tissue regeneration. Recent research from mouse models on HI has shown that the administration of lactate has a positive effect on recovery. In a paper published by our group it was discovered that the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1) plays and important role for cell proliferation and brain tissue repair after HI. This study has revealed that HCAR1 does not only play a role in cell proliferation after HI, but that it could also play a role in the survival of mature neurons. By immunostaining on brain sections from mice exposed to HI, we found that the density of neurons was significantly lower in mice that lacked the HCAR1 receptor. Since mitochondrial metabolism is closely linked to neuronal survival and apoptosis, we then used differentiated neurospheres to test the effect of lactate on mitochondrial density in neurons. However, our experiments did not show any effect of lactate on the density or number of neuronal mitochondria. Finally, we used western blotting to determine whether HCAR1 can influence the expression of mitochondrial proteins after HI. Our data suggested that mice lacking HCAR1 have a reduced expression of a mitochondrial protein involved in respiration, but more data points are needed to confirm this finding. Hence, it is also possible that HCAR1 could be involved in other metabolic processes such as regulating the cell’s energy metabolism and protein expression. Further research of HCAR1 in mouse models and in human tissue is important as this receptor as it is a therapeutic target for treatments against HI and possibly stroke in elderly people.

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