YME1L Controls the Accumulation of Respiratory Chain Subunits and is Required for Apoptotic Resistance, Cristae Morphogenesis, and Cell Proliferation

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2012 Jan 21

PMID 22262461

Citations 94

Authors

Lukas Stiburek

Jana Cesnekova

Olga Kostkova

Daniela Fornuskova

Kamila Vinsova

Laszlo Wenchich

Josef Houstek

Jiri Zeman

Affiliations

Soon will be listed here.

Abstract

Mitochondrial ATPases associated with diverse cellular activities (AAA) proteases are involved in the quality control and processing of inner-membrane proteins. Here we investigate the cellular activities of YME1L, the human orthologue of the Yme1 subunit of the yeast i-AAA complex, using stable short hairpin RNA knockdown and expression experiments. Human YME1L is shown to be an integral membrane protein that exposes its carboxy-terminus to the intermembrane space and exists in several complexes of 600-1100 kDa. The stable knockdown of YME1L in human embryonic kidney 293 cells led to impaired cell proliferation and apoptotic resistance, altered cristae morphology, diminished rotenone-sensitive respiration, and increased susceptibility to mitochondrial membrane protein carbonylation. Depletion of YME1L led to excessive accumulation of nonassembled respiratory chain subunits (Ndufb6, ND1, and Cox4) in the inner membrane. This was due to a lack of YME1L proteolytic activity, since the excessive accumulation of subunits was reversed by overexpression of wild-type YME1L but not a proteolytically inactive YME1L variant. Similarly, the expression of wild-type YME1L restored the lamellar cristae morphology of YME1L-deficient mitochondria. Our results demonstrate the importance of mitochondrial inner-membrane proteostasis to both mitochondrial and cellular function and integrity and reveal a novel role for YME1L in the proteolytic regulation of respiratory chain biogenesis.

Citing Articles

Deubiquitinating Enzymes Regulate Skeletal Muscle Mitochondrial Quality Control and Insulin Sensitivity in Patients With Type 2 Diabetes.

Dantas W, Heintz E, Zunica E, Mey J, Erickson M, Belmont K J Cachexia Sarcopenia Muscle. 2025; 16(2):e13763.

PMID: 40035128 PMC: 11876994. DOI: 10.1002/jcsm.13763.

Reactive oxygen species control protein degradation at the mitochondrial import gate.

McMinimy R, Manford A, Gee C, Chandrasekhar S, Mousa G, Chuang J Mol Cell. 2024; 84(23):4612-4628.e13.

PMID: 39642856 PMC: 11649020. DOI: 10.1016/j.molcel.2024.11.004.

Expression and functional implications of YME1L in nasopharyngeal carcinoma.

Cheng F, Huang H, Yin S, Liu J, Sun P Cell Death Dis. 2024; 15(6):423.

PMID: 38890304 PMC: 11189534. DOI: 10.1038/s41419-024-06811-6.

Role of Yme1 in mitochondrial protein homeostasis: from regulation of protein import, OXPHOS function to lipid synthesis and mitochondrial dynamics.

Kan K, Wilcock J, Lu H Biochem Soc Trans. 2024; 52(3):1539-1548.

PMID: 38864432 PMC: 11346431. DOI: 10.1042/BST20240450.

Targeting the mitochondrial protein YME1L to inhibit osteosarcoma cell growth in vitro and in vivo.

Sun X, Shi C, Dai J, Zhang M, Pei D, Yang L Cell Death Dis. 2024; 15(5):346.

PMID: 38769124 PMC: 11106333. DOI: 10.1038/s41419-024-06722-6.

References

Koppen M, Langer T . Protein degradation within mitochondria: versatile activities of AAA proteases and other peptidases. Crit Rev Biochem Mol Biol. 2007; 42(3):221-42. DOI: 10.1080/10409230701380452. View

Stiburek L, Zeman J . Assembly factors and ATP-dependent proteases in cytochrome c oxidase biogenesis. Biochim Biophys Acta. 2010; 1797(6-7):1149-58. DOI: 10.1016/j.bbabio.2010.04.006. View

Rabl R, Soubannier V, Scholz R, Vogel F, Mendl N, Vasiljev-Neumeyer A . Formation of cristae and crista junctions in mitochondria depends on antagonism between Fcj1 and Su e/g. J Cell Biol. 2009; 185(6):1047-63. PMC: 2711607. DOI: 10.1083/jcb.200811099. View

Coppola M, Pizzigoni A, Banfi S, Bassi M, Casari G, Incerti B . Identification and characterization of YME1L1, a novel paraplegin-related gene. Genomics. 2000; 66(1):48-54. DOI: 10.1006/geno.2000.6136. View

LUFT J . Permanganate; a new fixative for electron microscopy. J Biophys Biochem Cytol. 1956; 2(6):799-802. PMC: 2224005. DOI: 10.1083/jcb.2.6.799. View

Pecina P, capkova M, Chowdhury S, Drahota Z, Dubot A, Vojtiskova A . Functional alteration of cytochrome c oxidase by SURF1 mutations in Leigh syndrome. Biochim Biophys Acta. 2003; 1639(1):53-63. DOI: 10.1016/s0925-4439(03)00127-3. View

Stiburek L, Fornuskova D, Wenchich L, Pejznochova M, Hansikova H, Zeman J . Knockdown of human Oxa1l impairs the biogenesis of F1Fo-ATP synthase and NADH:ubiquinone oxidoreductase. J Mol Biol. 2007; 374(2):506-16. DOI: 10.1016/j.jmb.2007.09.044. View

Pejznochova M, Tesarova M, Hansikova H, Magner M, Honzik T, Vinsova K . Mitochondrial DNA content and expression of genes involved in mtDNA transcription, regulation and maintenance during human fetal development. Mitochondrion. 2010; 10(4):321-9. DOI: 10.1016/j.mito.2010.01.006. View

Lenaz G, Genova M . Structural and functional organization of the mitochondrial respiratory chain: a dynamic super-assembly. Int J Biochem Cell Biol. 2009; 41(10):1750-1772. DOI: 10.1016/j.biocel.2009.04.003. View

10.

Ehses S, Raschke I, Mancuso G, Bernacchia A, Geimer S, Tondera D . Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J Cell Biol. 2009; 187(7):1023-36. PMC: 2806285. DOI: 10.1083/jcb.200906084. View

11.

Tung B, Unger E, Levin B, Brasitus T, Getz G . Use of an unsaturated fatty acid auxotroph of Saccharomyces cerevisiae to modify the lipid composition and function of mitochondrial membranes. J Lipid Res. 1991; 32(6):1025-38. View

12.

Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko G, Rudka T . OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell. 2006; 126(1):177-89. DOI: 10.1016/j.cell.2006.06.025. View

13.

Rainey R, Glavin J, Chen H, French S, Teitell M, Koehler C . A new function in translocation for the mitochondrial i-AAA protease Yme1: import of polynucleotide phosphorylase into the intermembrane space. Mol Cell Biol. 2006; 26(22):8488-97. PMC: 1636789. DOI: 10.1128/MCB.01006-06. View

14.

Dunn C, Tamura Y, Sesaki H, Jensen R . Mgr3p and Mgr1p are adaptors for the mitochondrial i-AAA protease complex. Mol Biol Cell. 2008; 19(12):5387-97. PMC: 2592643. DOI: 10.1091/mbc.e08-01-0103. View

15.

Ugalde C, Coenen M, Farhoud M, Gilinsky S, Koopman W, van den Heuvel L . New perspectives on the assembly process of mitochondrial respiratory chain complex cytochrome c oxidase. Mitochondrion. 2005; 2(1-2):117-28. DOI: 10.1016/s1567-7249(02)00012-0. View

16.

Wan D, Gong Y, Qin W, Zhang P, Li J, Wei L . Large-scale cDNA transfection screening for genes related to cancer development and progression. Proc Natl Acad Sci U S A. 2004; 101(44):15724-9. PMC: 524842. DOI: 10.1073/pnas.0404089101. View

17.

Song Z, Chen H, Fiket M, Alexander C, Chan D . OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol. 2007; 178(5):749-55. PMC: 2064540. DOI: 10.1083/jcb.200704110. View

18.

Griparic L, Kanazawa T, van der Bliek A . Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J Cell Biol. 2007; 178(5):757-64. PMC: 2064541. DOI: 10.1083/jcb.200704112. View

19.

Walenga R, Lands W . Effectiveness of various unsaturated fatty acids in supporting growth and respiration in Saccharomyces cerevisiae. J Biol Chem. 1975; 250(23):9121-9. View

20.

Lenaers G, Reynier P, Elachouri G, Soukkarieh C, Olichon A, Belenguer P . OPA1 functions in mitochondria and dysfunctions in optic nerve. Int J Biochem Cell Biol. 2009; 41(10):1866-74. DOI: 10.1016/j.biocel.2009.04.013. View