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

Brendan Miller, Su Jeong Kim, Hemal H. Mehta, Kevin Cao, Hiroshi Kumagai, Neehar Thumaty, Naphada Leelaprachakul, Henry Jiao, Joan Vaughan, Jolene Diedrich, Alan Saghatelian, Thalida E. Arpawong, Eileen M. Crimmins, Nilüfer Ertekin-Taner, Meral A. Tubi, Evan T. Hare, Meredith N. Braskie, Léa Décarie-Spain, Scott E. Kanoski, Francine GrodsteinDavid A. Bennett, Lu Zhao, Arthur W. Toga, Junxiang Wan, Kelvin Yen, Pinchas Cohen

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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