Evidence map›Paper›PMID 41891014›Full record

ArticlemedRxiv : the preprint server for health sciences2026

Multi-omics liquid biopsy identifies mitochondrial dysfunction in geographic atrophy and supports the longevity-associated metabolite α-ketoglutarate as a therapeutic strategy.

Tsai-Chu Yeh, Gabriel Velez, Architesh Prasad, Soo Hyeon Lee, Ditte K Rasmussen, Aarushi Kumar, Madhumeeta Chadha, Mohamed Ziad Dabaja, Aneal M Singh, Steven Sanislo and 7 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in medRxiv : the preprint server for health sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Tsai-Chu YehMolecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA.
Gabriel VelezMolecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA.
Architesh PrasadMolecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA.
Soo Hyeon LeeMolecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA.
Ditte K RasmussenMolecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA.
Aarushi KumarMolecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA.
Madhumeeta ChadhaMolecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA.
Mohamed Ziad DabajaDepartments of Physiology and Pharmacology & Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada.
Aneal M SinghMolecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA.
Steven SanisloDepartment of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA.
Stephen SmithDepartment of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA.
Prithvi MryuthyunjayaMolecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA.
Artis MontagueDepartment of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA.
Alexander G BassukStead Family Department of Pediatrics and Neurology, The Iowa Neuroscience Institute, The HAWKEYE-IDDRC, The University of Iowa Carver College of Medicine.
David AlmeidaErie Retina Research & Center for Advanced Surgical Exploration, Erie, PA, 16505. USA.
Antoine DufourDepartments of Physiology and Pharmacology & Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada.
Vinit B MahajanMolecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA.

Funding

Stanford Vision Research CoreP30EY026877 · NEI · STANFORD UNIVERSITY · PI Jeffrey L Goldberg · 2017 to 2026
$8.0M
Improving rigor and reproducibility in adaptive optics ophthalmoscopyR01EY031360 · NEI · STANFORD UNIVERSITY · PI DUBRA, ALFREDO · 2020 to 2023
$2.3M
Stanford Vision Training ProgramT32EY027816 · NEI · STANFORD UNIVERSITY · PI Jeffrey L Goldberg · 2018 to 2026
$2.0M
Inflammatory Gene Transcription in the RetinaR01EY030151 · NEI · STANFORD UNIVERSITY · PI BASSUK, ALEXANDER G, MAHAJAN, VINIT B · 2020 to 2024
$2.0M
Proteomic Biomarkers of Intraocular InfectionR01EY031952 · NEI · STANFORD UNIVERSITY · PI BASSUK, ALEXANDER G, FERGUSON, POLLY J · 2020 to 2023
$1.6M
Stanford Ophthalmology Advanced Research ProgramR38EY037090 · NEI · STANFORD UNIVERSITY · PI Yang Sun · 2025 to 2026
$495k
NEI NIH HHS P30 EY026877NEI NIH HHS R01 EY030151NEI NIH HHS R01 EY031360NEI NIH HHS R01 EY031952NEI NIH HHS R38 EY037090NEI NIH HHS T32 EY027816
6 · The paper itself

Abstract

Background: Mitochondrial dysfunction is an emerging metabolic hallmark of age-related diseases, yet tools to directly profile mitochondrial pathways and test metabolic interventions in the living human eye remain limited. Multi-omics ocular liquid biopsy enables real-time proteomic and metabolomic profiling of the intraocular microenvironment, complementing systemic biomarkers and imaging surrogates. Here, we used this approach to define mitochondrial and tricarboxylic acid (TCA) cycle dysregulation in geographic atrophy (GA) and to assess whether oral α-ketoglutarate (α-KG) supplementation can modulate mitochondrial metabolites within the eye. Methods: Mitochondrial and TCA cycle-related proteins were profiled in aqueous humor (AH) samples from patients with GA using DNA-aptamer-based proteomics. In a phase 0 study, a second cohort undergoing sequential cataract surgery provided paired AH samples collected at first-eye surgery and at second-eye surgery after interim α-KG supplementation. These samples underwent targeted metabolomic profiling using hydrophilic interaction liquid chromatography coupled with mass spectrometry. Results: In GA, 64 mitochondrial proteins were differentially expressed, including coordinated TCA-cycle deficiencies marked by reduced expression of enzymes regulating TCA entry and flux, including PDHB and DLST. In the phase 0 cohort, oral α-KG supplementation significantly increased intraocular α-KG levels and the α-KG-to-succinate ratio (P < 0.05), with coordinated shifts across TCA intermediates consistent with enhanced TCA cycle flux. Conclusions: AH proteomics demonstrated mitochondrial pathway depletion in GA, consistent with reduced oxidative bioenergetic capacity. AH metabolomics provided first-in-human in vivo evidence that systemic α-KG supplementation can modify intraocular metabolites and may enhance intraocular energy metabolism. These findings support ocular liquid biopsy as a precision-health framework for per-patient biomarker-guided metabolic trials in GA.

Indexed as

Age-related macular degenerationAlpha-ketoglutarateAqueous HumorGeographic AtrophyLiquid BiopsyMetabolomicsMitochondriaProteomicsSystemic Metabolic InterventionsTricarboxylic Acid Cycle

Identifiers

PMID41891014
PMCPMC13015626

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.