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Mitochondrial DNA variation in Alzheimer’s disease reveals a unique microprotein called SHMOOSE

Molecular Psychiatry volume 28, pages 1813–1826 (2023)Cite this article

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A Correction to this article was published on 20 January 2023

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Abstract

Mitochondrial DNA variants have previously associated with disease, but the underlying mechanisms have been largely elusive. Here, we report that mitochondrial SNP rs2853499 associated with Alzheimer’s disease (AD), neuroimaging, and transcriptomics. We mapped rs2853499 to a novel mitochondrial small open reading frame called SHMOOSE with microprotein encoding potential. Indeed, we detected two unique SHMOOSE-derived peptide fragments in mitochondria by using mass spectrometry—the first unique mass spectrometry-based detection of a mitochondrial-encoded microprotein to date. Furthermore, cerebrospinal fluid (CSF) SHMOOSE levels in humans correlated with age, CSF tau, and brain white matter volume. We followed up on these genetic and biochemical findings by carrying out a series of functional experiments. SHMOOSE acted on the brain following intracerebroventricular administration, differentiated mitochondrial gene expression in multiple models, localized to mitochondria, bound the inner mitochondrial membrane protein mitofilin, and boosted mitochondrial oxygen consumption. Altogether, SHMOOSE has vast implications for the fields of neurobiology, Alzheimer’s disease, and microproteins.

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Fig. 1: Mitochondrial rs2853499 predicts AD risk and parahippocampus thickness.
Fig. 2: Endogenous SHMOOSE is detected in mitochondria.
Fig. 3: Unique features of the SHMOOSE amino acid sequence.
Fig. 4: SHMOOSE levels correlate with AD-related biomarkers and brain white matter.
Fig. 5: Direct actions of SHMOOSE on brain gene expression.
Fig. 6: SHMOOSE interacts with mitofilin and modifies mitochondrial biology.
Fig. 7: SHMOOSE expression in human Alzheimer’s disease brains and activity in neuronal models of amyloid beta toxicity.
Fig. 8: Bulk gene expression differences between SHMOOSE and mutant D47N indicate altered function.

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Acknowledgements

The study was supported by NIH grants P30AG10161, P30AG072975, R01AG15819, R01AG17917, U01AG61356, R01AG069698, RF1AG061834, R01AG068405, P30AG068345, P01AG055369, DK118402, F31 AG059356, and T32 AG00037; as well as The Quebec Research Funds Postdoctoral Fellowship, Royal Golden Jubilee Ph.D. Program, and Miriam and Merle Hinrich Mitochondrial DNA Research Fund. Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

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Authors and Affiliations

  1. Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA

    Brendan Miller, Su-Jeong Kim, Hemal H. Mehta, Kevin Cao, Hiroshi Kumagai, Neehar Thumaty, Naphada Leelaprachakul, Regina Gonzalez Braniff, Henry Jiao, Thalida E. Arpawong, Eileen M. Crimmins, Junxiang Wan, Kelvin Yen & Pinchas Cohen

  2. Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA

    Brendan Miller & Scott E. Kanoski

  3. Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA, USA

    Joan Vaughan, Jolene Diedrich & Alan Saghatelian

  4. Mayo Clinic, Department of Neuroscience, Jacksonville, FL, USA

    Nilüfer Ertekin-Taner

  5. Imaging Genetics Center, Institute for Neuroimaging and Informatics, University of Southern California, Los Angeles, CA, USA

    Meral A. Tubi, Evan T. Hare & Meredith N. Braskie

  6. Department of Neurology, University of Southern California, Los Angeles, CA, USA

    Meral A. Tubi, Evan T. Hare & Meredith N. Braskie

  7. Human and Evolutionary Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, USA

    Léa Décarie-Spain & Scott E. Kanoski

  8. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

    Francine Grodstein & David A. Bennett

  9. Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA

    Lu Zhao & Arthur W. Toga

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  1. Brendan Miller
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Consortia

for the Alzheimer’s Disease Neuroimaging Initiative*

Contributions

BM conceived and designed analyses, collected data, performed analyses, and wrote the paper. SK conceived experimental design. HM collected data. KC collected data. HK collected data. NT collected data. NL conceived experimental design. HJ contributed analysis tools. JV contributed experimental design and collected data. JD collected data. AS conceived experimental design. TA contributed analysis tools. EC contributed analysis tools. NE-T contributed analysis tools. MT carried out analyses. EH carried out analyses. MB conceived analysis design. LD-S carried out animal studies. SK conceived experimental design. FG collected data. DB contributed analysis tools. LZ carried out analyses. AT contributed analysis tools. JW designed experimental tools and carried out experiments. KY conceived analyses. PC conceived and designed analyses and contributed to manuscript preparation.

Corresponding author

Correspondence to Pinchas Cohen.

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Competing interests

Intellectual property related to SHMOOSE has been filed by the University of Southern California.

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The original online version of this article was revised: In the by-line of this article, the following phrase was missing: Include the phrase “for the Alzheimer’s Disease Neuroimaging Initiative*.

In the by-line of this article, the following author was missing: Regina Gonzalez Braniff.

In the methods section of this article, the following text was missing: “Data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). The ADNI was launched in 2003 as a public-private partnership, led by Principal Investigator Michael W. Weiner, MD. The primary goal of ADNI has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer’s disease (AD)”..

In the Acknowledgements section of this article the following text was missing: “Data collection and sharing for this project was funded by the Alzheimer’'s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California”.

In the sentence beginning “rs2853499 (henceforth referred to as SHMOOSE.D47N)…” in this article, the typo “from glutamine to aspartic acid” should read “from aspartic acid to asparagine”. The original article has been corrected.

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Miller, B., Kim, SJ., Mehta, H.H. et al. Mitochondrial DNA variation in Alzheimer’s disease reveals a unique microprotein called SHMOOSE. Mol Psychiatry 28, 1813–1826 (2023). https://doi.org/10.1038/s41380-022-01769-3

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