Novel roles of the mitochondrial presequence processing machinery in health and disease

• Applicant: Professorin Dr. Friederike-Nora Vögtle
• Subject Area: Biochemistry ; Cell Biology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289336601

• Final Report Year: 2022

Final Report Abstract

The aim of this Emmy-Noether project was the comprehensive analysis of the mitochondrial presequence processing machinery under physiological conditions and the investigation of specific pathophysiological aspects as mutations in several subunits have been associated with severe human diseases. Presequences are targeting signals that mediate the import of mitochondrial precursor proteins into the organelle after their synthesis on cytosolic ribosomes. The presequence processing machinery consists of processing proteases that cleave the presequence (MPP, Icp55, Oct1/MIP) and presequence peptidases (Cym1/PreP, Ste23, Prd1) that degrade the presequence. In my Emmy-Noether group we uncovered the peptidases Ste23 and Prd1 and their function in presequence peptide degradation. We also characterized the role of the human homologue Cym1 (PreP) and consequences of defective PreP presequence turnover in human cells (Aim 3). Together with clinicians we identified and described the first patients with mutations in the catalytic subunit of MPP and showed that the patients have defects in functions of iron-sulfur cluster containing proteins (Aim 2). Finally, as proposed in Aim 1 we thoroughly characterized the unfolded protein response that protects yeast upon defects in MPP and identified two key protective mechanisms on the molecular level: The maintenance of mitochondrial gene expression by the transcription factor Rox1 and the role of protein import and lipid remodelling to maintain protein import upon mitochondrial stress conditions.

Publications

• (2016) MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death. Genome Med. 8: 106
  Eldomery MK, Akdemir ZC, Vögtle FN, Charng WL, Mulica P, Rosenfeld JA, Gambin T, Gu S, Burrage LC, Al Shamsi A, Penney S, Jhangiani SN, Zimmerman HH, Muzny DM, Wang X, Tang J, Medikonda R, Ramachandran PV, Wong LJ, Boerwinkle E, Gibbs RA, Eng CM, Lalani SR, Hertecant J, Rodenburg RJ, Abdul- Rahman OA, Yang Y, Xia F, Wang MC, Lupski JR, Meisinger C, Sutton VR
  (See online at https://doi.org/10.1186/s13073-016-0360-6)
• (2017) Landscape of submitochondrial protein distribution. Nat Commun. 8: 290
  Vögtle FN, Burkhart JM, Gonczarowska-Jorge H, Kücükköse C, Taskin AA, Kopczynski D, Ahrends R, Mossmann D, Sickmann A, Zahedi RP, Meisinger C
  (See online at https://doi.org/10.1038/s41467-017-00359-0)
• (2017) The novel mitochondrial matrix protease Ste23 is required for efficient presequence degradation and processing. Mol. Biol. Cell 28: 997-1002
  Taskin AA, Kücükköse C, Burger N, Mossmann D, Meisinger C, Vögtle FN
  (See online at https://doi.org/10.1091/mbc.e16-10-0732)
• (2018) Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood. Am J Hum Genet. 102: 557-573
  Vögtle FN, Brändl B, Larson A, Pendziwiat M, Friederich MW, White SM, Basinger A, Kücükköse C, Muhle H, Jähn JA, Keminer O, Helbig KL, Delto CF, 1 Myketin L, Mossmann D, Burger N, Miyake N, Burnett A, van Baalen A, Lovell MA, Matsumoto N, Walsh M, Yu HC, Shinde DN, Stephani U, Van Hove JLK, Müller FJ, Helbig I
  (See online at https://doi.org/10.1016/j.ajhg.2018.02.014)
• (2018) The Enzymatic Core of the Parkinson's Disease- Associated Protein LRRK2 Impairs Mitochondrial Biogenesis in Aging Yeast. Front. Mol. Neurosci. 11: 205
  Aufschnaiter A, Kohler V, Walter C, Tosal-Castano S, Habernig L, Wolinski H, Keller W, Vögtle FN, Büttner S
  (See online at https://doi.org/10.3389/fnmol.2018.00205)
• (2020) An Early mtUPR: Redistribution of the Nuclear Transcription Factor Rox1 to Mitochondria Protects against Intramitochondrial Proteotoxic Aggregates. Mol. Cell 77: 180-188
  Poveda-Huertes D, Matic S, Marada A, Habernig L, Licheva M, Myketin L, Gilsbach R, Tosal-Castano S, Papinski D, Mulica P, Kretz O, Kücükköse C, Taskin AA, Hein L, Kraft C, Büttner S, Meisinger C, Vögtle F
  (See online at https://doi.org/10.1016/j.molcel.2019.09.026)
• (2021) Functional coupling of presequence processing and degradation in human mitochondria. FEBS J. 288: 600-613
  Kücükköse C, Taskin AA, Marada A, Brummer T, Dennerlein S, Vögtle FN
  (See online at https://doi.org/10.1111/febs.15358)
• (2021) Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery. Nat. Commun. 12: 4284
  Walter C, Marada A, Suhm T, Ernsberger R, Muders V, Kücükköse C, Sánchez- Martín P, Hu Z, Aich A, Loroch S, Solari FA, Poveda-Huertes D, Schwierzok A, Pommerening H, Matic S, Brix J, Sickmann A, Kraft C, Dengjel J, Dennerlein S, Brummer T, Vögtle FN, Meisinger C
  (See online at https://doi.org/10.1038/s41467-021-24426-9)
• (2021) Increased mitochondrial protein import and cardiolipin remodelling upon early mtUPR. PLoS Genet. 17: e1009664
  Poveda-Huertes D, Taskin AA, Dhaouadi I, Myketin L, Marada A, Habernig L, Büttner S, Vögtle FN
  (See online at https://doi.org/10.1371/journal.pgen.1009664)
• (2021) Open questions on the mitochondrial unfolded protein response. FEBS J. 288: 2856-2869
  Vögtle FN
  (See online at https://doi.org/10.1111/febs.15569)