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Heterogeneous brain region-specific responses to astrocytic mitochondrial DNA damage in mice

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Ayala, Daniela A., Matarazzo, Anthony, Seaberg, Bonnie L., Patel, Misha, Tijerina, Eliana, Matthews, Camryn, Bizi, Gabriel, Brown, Ashton +3 more·2024·Scientific Reports
DOI 10.1038/s41598-024-69499-wPMC PMC11316820
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Abstract

ABSTRACT Astrocytes use Ca 2+ signals to regulate multiple aspects of normal and pathological brain function. Astrocytes display context-specific diversity in their functions, and in their response to noxious stimuli between brain regions. Indeed, astrocytic mitochondria have emerged as key players in governing astrocytic functional heterogeneity, given their ability to dynamically adapt their morphology to regional demands on their ATP generation and Ca 2+ buffering functions. Although there is reciprocal regulation between mitochondrial dynamics and mitochondrial Ca 2+ signaling in astrocytes, the extent of this regulation into the rich diversity of astrocytes in different brain regions remains largely unexplored. Brain-wide, experimentally induced mitochondrial DNA (mtDNA) loss in astrocytes showed that mtDNA integrity is critical for proper astrocyte function, however, few insights into possible diverse responses to this noxious stimulus from astrocytes in different brain areas were reported in these experiments. To selectively damage mtDNA in astrocytes in a brain-region-specific manner, we developed a novel adeno-associated virus (AAV)-based tool, Mito-PstI, which expresses the restriction enzyme PstI, specifically in astrocytic mitochondria. Here, we applied Mito-PstI to two distinct brain regions, the dorsolateral striatum, and the hippocampal dentate gyrus, and we show that Mito-PstI can induce astrocytic mtDNA loss in vivo , but with remarkable brain-region-dependent differences on mitochondrial dynamics, spontaneous Ca 2+ fluxes and astrocytic as well as microglial reactivity. Thus, AAV-Mito-PstI is a novel tool to explore the relationship between astrocytic mitochondrial network dynamics and astrocytic mitochondrial Ca 2+ signaling in a brain-region-selective manner.

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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 Ayala et al. 2024

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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 Ayala et al. 2024

    The Results section reports that astrocytic mitochondria in the dentate gyrus are smaller and less abundant than those in the DLS, supporting a regional morphological contrast. The paper does not describe DLS mitochondria as fusiform or compare either region’s mitochondria with those in the SNc. Page numbers were not available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The AAV Mito-PstI expresses PstI under control of the astrocyte-specific GfaABC1D promoter, is directed to the astrocytic mitochondrial matrix by a mito7 targeting signal, and cuts mitochondrial DNA at PstI recognition sites, thereby damaging mtDNA only in astrocytes within pre-specified Mito-PstI injected brain regions in vivo.

    “Our novel AAV called Mito-PstI, expresses the restriction enzyme PstI under control of the astrocyte-specific GfaABC1D promoter.”

    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 Ayala et al. 2024

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Cited by

Sorted by citations

Authors
Ayala, D. A., Matarazzo, A., Seaberg, B. L., Patel, M., Tijerina, E., Matthews, C., Bizi, G., Brown, A., Ta, A., Rimer, M., & Srinivasan, R.
Affiliations
Texas A&M University (US)
Corresponding author
  • Rimer, Mendell
  • Srinivasan, Rahul
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2024-08-10
Volume
14
Issue
1
Pages
18586-18586
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-024-69499-w
PMC
PMC11316820
OpenAlex
W4401483195
Cited by
7
References
2
Citations by year
2026: 4 · 2025: 3
FWCI
0.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (T32 GM135115)
  • National Institutes of Health,United States (T32 GM135748)
  • National Institute of Neurological Disorders and Stroke (R21 NS121959)
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
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
astrocytes, mitochondrial DNA damage, brain region specificity, mitochondrial dynamics, mitochondrial calcium signaling, dorsolateral striatum, dentate gyrus, microglial activation

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