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Cited by 31Mitochondrial Function and PathologyNeuroscience and Neuropharmacology ResearchIon Channels and Receptors

Astrocytic mitochondria in adult mouse brain slices show spontaneous calcium influx events with unique properties

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Huntington, Taylor E., Srinivasan, Rahul·2021·Cell Calcium
DOI 10.1016/j.ceca.2021.102383

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Abstract

Astrocytes govern critical aspects of brain function via spontaneous calcium signals in their soma and processes. A significant proportion of these spontaneous astrocytic calcium events are associated with mitochondria, however, the extent, sources, or kinetics of astrocytic mitochondrial calcium influx have not been studied in the adult mouse brain. To measure calcium influx into astrocytic mitochondria in situ, we generated an adeno-associated virus (AAV) with the astrocyte-specific GfaABC 1 D promoter driving expression of the genetically encoded calcium indicator, GCaMP6f tagged to mito7, a mitochondrial matrix targeted signal sequence. Using this construct, we observed AAV-mediated expression of GCaMP6f in adult mouse astrocytic mitochondria that co-localized with MitoTracker deep red (MTDR) in the dorsolateral striatum (DLS) and in the hippocampal stratum radiatum (HPC). Astrocytic mitochondria co-labeled with MTDR and GCaMP6f displayed robust, spontaneous calcium influx events in situ, with subcellular differences in calcium influx kinetics between somatic, branch, and branchlet mitochondria, and inter-regional differences between mitochondria in DLS and HPC astrocytes. Calcium influx into astrocytic mitochondria was strongly dependent on endoplasmic reticulum calcium stores, but did not require the mitochondrial calcium uniporter, MCU. Exposure to either glutamate, D1 or D2 dopamine receptor agonists increased calcium influx in some mitochondria, while simultaneously decreasing calcium influx in other mitochondria from the same astrocyte. These findings show that astrocytic mitochondria possess unique properties with regard to their subcellular morphology, mechanisms of calcium influx, and responses to neurotransmitter receptor agonists. Our results have important implications for understanding the role of astrocytic mitochondria during pathological processes.

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  • Mitochondria in central nervous system astrocytes are strategically distributed within subcellular regions in the astrocytic territory, endfeet and soma, and since astrocytes generally outnumber neurons in the CNS, astrocytic mitochondria are optimally positioned to cater to the high energy demands of CNS neurons, particularly substantia nigra pars compacta dopaminergic neurons.

    “Mitochondria in CNS astrocytes are strategically distributed within subcellular regions in the astrocytic territory, endfeet and soma”

    From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as Huntington and Srinivasan 2021

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  • The morphology of astrocytic mitochondria in the SNc is distinct from the fusiform morphology previously reported in DLS astrocytes and resembles astrocytic mitochondria in the dentate gyrus of the hippocampus.

    “This distinct morphology is in stark contrast to the fusiform morphology of mitochondria previously reported by us in DLS astrocytes and resembles astrocytic mitochondria in the dentate gyrus of the hippocampus (Ayala et al. 2024; Huntington and Srinivasan 2021).”

    From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as Huntington and Srinivasan 2021

    The sections on DLS mitochondrial size and on DLS–hippocampus differences report morphological variation in DLS astrocytes and compare DLS with hippocampal CA1 astrocytes (pages not supplied). They do not describe DLS mitochondria as fusiform or examine dentate gyrus or SNc mitochondria, so they cannot establish the specific resemblance and contrast claimed. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Astrocytic mitochondria are highly active organelles, displaying a wide panorama of Ca2+ influx events that robustly respond to neurotransmitter agonists.

    “Astrocytic mitochondria are highly active organelles, displaying a wide panorama of Ca2+ influx events that robustly respond to neurotransmitter agonists”

    From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as Huntington and Srinivasan 2021

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Cited by

Sorted by citations

Authors
Huntington, T. E., & Srinivasan, R.
Affiliations
Texas A&M University (US)
Corresponding author
Srinivasan, Rahul
ORCID
Srinivasan, Rahul
Venue
Cell Calcium
Publisher
Elsevier BV
Published
2021-06
Volume
96
Pages
102383
ISSN
0143-4160 (ISSN-L)
DOI
10.1016/j.ceca.2021.102383
OpenAlex
W3130463185
Cited by
31
References
8
Citations by year
2026: 6 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 3
FWCI
1.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Calcium (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
Funders
  • Texas A&M University Health Sciences Center
  • NSF
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
astrocytes, mitochondrial calcium uptake, GCaMP6f, endoplasmic reticulum calcium stores, mitochondrial calcium uniporter, glutamate, dopamine D1 receptor, dopamine D2 receptor, striatum, hippocampus, AAV gene delivery
MeSH terms
Age Factors, Animals, Astrocytes, Brain, Calcium, Female, Male, Mice, Inbred C57BL, Mitochondria, Organ Culture Techniques, Mice, Knockout, Dopamine Agonists, Glutamic Acid, Mice

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