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Blood and neuronal extracellular vesicle mitochondrial disruptions in schizophrenia

Neuropsychopharmacology (2025)Cite this article

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Abstract

The high energy demand of the human brain obligates robust mitochondrial energy metabolism, while mitochondrial dysfunctions have been linked to neuropsychiatric disorders, including schizophrenia spectrum disorders (SSD). However, in vivo assessments that can directly inform brain mitochondrial functioning and its etiopathophysiological path to SSD remain difficult to obtain. We hypothesized that system and brain mitochondrial dysfunctions in SSD may be indexed by elevated cell-free mitochondrial DNA (cf-mtDNA) levels in the blood and in neuronal extracellular vesicles (nEVs). We also explored if these mtDNA marker elevations were associated with brain metabolites as measured by magnetic resonance spectroscopy (MRS). We examined blood cf-mtDNA in 58 SSD patients and 33 healthy controls, followed by assessing nEV mtDNA and metabolite levels using MRS in a subgroup of patients and controls. We found that people with SSD had significantly elevated cf-mtDNA levels in both the blood (p = 0.0002) and neuronal EVs (p = 0.003) compared to controls. These mtDNA abnormalities can be linked back to brain lactate+ levels such that higher blood and nEV mtDNA levels were significantly associated with higher lactate+ levels measured at the anterior cingulate cortex (r = 0.53, 0.53; p = 0.008, 0.03, respectively) in SSD patients. Furthermore, higher developmental stress and trauma were significantly associated with higher cf-mtDNA levels in both the blood and neuronal EVs in SSD patients (r = 0.29, 0.49; p = 0.01, 0.03, respectively). In conclusion, if replicated and fully developed, blood and neuronal EV-based cell-free mtDNA may provide a clinically accessible biomarker to more directly evaluate the mitochondrial hypothesis and the abnormal bioenergetics pathways in schizophrenia.

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Fig. 1: Cell free Blood mtDNA and neuronal EV characterization in SSD as compared to healthy controls.
Fig. 2: ACC Metabolite Alterations and Associations with Blood and EVs cf-mtDNA.
Fig. 3: Blood and Neuronal EV cf-mtDNA Correlate with ACC Lactate+ in SSD Patients and Healthy Controls.
Fig. 4: Childhood Stress Correlations with Blood and EV cf-mtDNA in SSD Patients and Healthy Controls.

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The datasets generated and analyzed here are currently not publicly available, but we will strive to honor data request on case-by-case basis.

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Funding

Funding support was received from NIH grants R01MH133812, R01MH116948, R01MH112180 (LEH), MH120876 and MH128771 (AP).

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  1. These authors contributed equally: A. Ankeeta, Ashutosh Tripathi.

  2. These authors jointly supervised this work: Anilkumar Pillai, L. Elliot Hong.

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    A. Ankeeta, Ashutosh Tripathi, Bindu Pillai, Yizhou Ma, Jessica N. Jernberg, Keiko Kunitoki, Xiaoming Du, Si Gao, Bhim M. Adhikari, Consuelo Walss-Bass, Giselli Scaini, Peter Kochunov, Anilkumar Pillai & L. Elliot Hong

  2. University of Maryland School of Medicine, Baltimore, MD, USA

    Joshua J. Chiappelli

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AA, AT, AKP and LEH wrote the paper; LEH and AKP obtained funding. AA, AT, BP, YM, JJC, SI, BA, and PK contributed to data collection, processing, and/or analysis, all contributed to manuscript editing, critical revision, and approved the final version of the manuscript.

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LEH has received or plans to receive research funding or consulting fees on research projects from Mitsubishi, Your Energy Systems LLC, Neuralstem, Taisho, Heptares, Pfizer, Luye Pharma, IGC Pharma, Sound Pharma, Regeneron, Takeda, and Alto Neuroscience. Other authors declare no conflicts of interest with respect to this work.

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Ankeeta, A., Tripathi, A., Pillai, B. et al. Blood and neuronal extracellular vesicle mitochondrial disruptions in schizophrenia. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02204-1

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