Mitochondrial Quality Control

Transcription

1 Mitochondrial Quality Control Oleh Khalimonchuk, Ph.D. Graduate Course 2214/BIOC 998 Stockholm, May 16, 2017

2 Respiration (ATP generation) Cofactors & key metabolites synthesis Ion homeostasis Lipid homeostasis ROS production/signaling Regulation of apoptosis Yeast Human Mitochondria are semi-autonomous organelles involved in a variety of vital cellular processes Sustaining normal mitochondrial function is critical as mitochondria are not produced de novo microcopyu.com

3 Composed of 1,000-1,500 proteins, majority of which are synthesized in the cytosol and imported into the organelle A small fraction of proteins (8-13) originates from the organelle s own genome The inner membrane is extremely protein-rich and is one of the major sites of essential mitochondrial functions Bohovych et al., Antiox. Redox Signal. (2015)

4 What can go wrong in a mitochondrion? Extensive ROS production by mitochondrial respiratory iiichain (MRC) can damage proteins and mtdna which iiiare in the close proximity to the MRC Improperly assembled redox cofactors can act as proiiioxidants (inherent ability to generate ROS via Fenton iiireactions ) Mismatches in subunits stoichiometry may lead to iiiaccumulation of unassembled/misfolded proteins Khalimonchuk et al., J. Biol. Chem. (2007); Khalimonchuk et al., J. Biol. Chem. (2012); Bohovych et al., Antioxid. Redox Signal. (2015)

5 Mitochondrial dysfunction - the road to ruin Nuclear DNA mutations mtdna mutations Misfolded proteins ROS MRC dysfunction Impaired mitochondrial dynamics Ca 2+ overload Impaired cellular energetics Cellular damage/death Cancers: Gliomas Lymphomas Neurological: Leigh syndrome Leukodystrophy Optic nerve atrophy Ataxias Neurodegenerative: Parkinsonism ALS Cardiovascular: Cardiomyopathies Peripheral artery disease and Aging Levytskyy et al., J. Neuroimmune Pharm. (2016) Vafai and Mootha, Nature (2012)

6 We re doomed!!! or are we?

7 Biogenesis Dynamics: fission/fusion Mitophagy Respiration (ATP generation) Cofactor synthesis Ion homeostasis Lipid homeostasis ROS production/signaling Regulation of apoptosis ROS scavenging Protein quality control repair/refolding/degradation DNA repair Multiple mechanisms are involved in sustaining of normal mitochondrial function Adapted from Figge et al., Bioessays (2013)

8 Mitochondrial quality control (MQC) Two levels of MQC: 1). Organellar 2). Molecular (aka intramitochondrial) Molecular and organellar MQC are interdependent and functionally intertwined Rugarli & Langer, EMBO J. (2012)

9 Organellar MQC fusion Mitochondrial content mixing via fusion helps to dilute the damage Fusion No fusion Youle & van der Bliek, Science (2012) Tsushima et al. (submitted)

10 Organellar MQC fusion OM fusion IM fusion OM and IM fusion are coordinated but physically separate events Charcot-Marie-Tooth Syndrome Dominant Optic Atrophy Detmer & Chan, Nat. Rev. Mol. Cell. Biol. (2007); Ishihara et al., Antioxid. Redox Signal. (2013); Wai & Langer, Trends Endocrin. Metab. (2016) Ubiquitination Phosphoylation SUMOylation Thiol oxidation

11 Organellar MQC fusion SIMH = Stress-induced mitochondrial hyperfusion SIMH relies on thiol oxidation of the conserved cysteine residues in Mfn1/2 Anand et al., BBA (2013); Wai & Langer, Trends Endocrin. Metab. (2016)

12 Organellar MQC fission Neurodegeneration Myocardial Infarction ER Mito Dnm1/Drp1 rings Otera & Mihara, J. Biochem. (2011); Hoppins & Nunnari, Science (2013); Wai & Langer, Trends Endocrin. Metab. (2016)

13 Organellar MQC - mitophagy Parkinsonism Youle & van der Bliek, Science (2012); Escobar-Henriques & Langer EMBO Rep. (2014) Damaged mitochondria can be segregated through fission and eliminated by mitophagy

14 Organellar MQC mitochondria-derived vesicles Anand et al., BBA (2013); Soubannier et al., PLoS One (2013); Bohovych et al., Antioxid. Redox Signal. (2015) Mitochondria-derived vesicles recently identified non-mitophagy clearance mechanism

15 Organellar/Molecular MQC UPS delivers Several other factors appear to work in parallel or concomitantly with PINK1/Parkin system (MITOL, MULAN, Mdm30, Vms1, DJ-1, etc.) MITOL, MULAN and Mdm30 are ubiquitin ligases involved mitochondria-associated degradation (MAD) Paget s disease ALS Anand et al., BBA (2013)

16 Organellar/Molecular MQC playing tag with mitochondria Vms1 is an auxiliary factor that tags damaged mitochondria and helps to recruit UPS machinery Heo et al., Mol. Cell (2010); Iryna Bohovych (unpublished) When neither hyperfusion, nor mitophagy can help cells undergo apoptosis

17 Molecular MQC - Proteases Hi there Removal of misfolded, damaged or non-assembled polypeptides Central roles in: mitochondrial biogenesis mitochondrial dynamics mitochondrial signaling lipid homeostasis apoptosis Bohovych et al., Antioxid. Redox Signal. (2015)

18 Molecular MQC - Proteases Two major classes of IMQC proteases: 1). ATP-dependent (AAA+ proteases) 2). ATP-independent Sauer & Baker, Annu. Rev. Biochem (2011); Levytskyy et al., J. Neuroimmune Pharm. (2016)

19 Molecular MQC - Proteases Parkinsonism HFD-induced obesity Amyotrophic Lateral Sclerosis Dilated cardiomyopathy Mental Retardation CORDAS syndrome Hereditary Spastic Paraplegia Spinocerebellar Ataxia type 28 Spastic Ataxia-Neuropathy Syndrome Parkinsonism Genetic interactions indicate tight functional coupling between MQC proteases Bohovych et al., J. Biol. Chem (2014)

20 Molecular MQC in the matrix Matrix MQC involves both soluble and mitochondrial inner membrane anchored proteases Removal of processed mitochondrial targeting signal peptides is yet another critical aspect of the matrix MQC Levytskyy et al., J. Neuroimmune Pharm. (2016) Alzheimer s disease

21 Molecular MQC in the IM and IMS Proteolytic processing Regulatory proteolysis Proteolytic removal of damaged proteins Adapted from Anand et al., BBA (2013)

22 Where molecular and organellar MQC intersect Stress-triggered cleavage of L- OPA1 by activated OMA1 protease stimulates fission and leads to metabolic re-tuning Control -DY ROS Heat stress Hypoxia (?) Oma1 MO Quiros et al., EMBO J. (2012); Bohovych et al., Sci. Rep. (2015); Wai & Langer, Trends Endocrin. Metab. (2016)

23 Where molecular and organellar MQC intersect PINK1 accumulation is a consequence of its attenuated turnover by PARL protease Anand et al., BBA (2013)

24 Mitochondrion to nucleus communication Retrograde responses Various signals are produced by mitochondria to communicate their functional states AMPK ROS, Ca 2+, ATP/ADP, NAD + /NADH Ac-CoA/Citrate Succinate/Fumarate (ATP/ADP) LON, m-aaa and likely Oma1 proteases participate in modulation of mitochondrial ROS and Ca 2+ levels TORC1 NRF2L MAPK Sirtuins HIF1a HIF1a (ROS) (NAD + /NADH; Ac-CoA) (Succinate/Fumarate)

25 Mitochondrion to nucleus communication - Metabolites Certain mitochondrial metabolites can be transported outside of the organelle and impinge on several signaling pathways or elicit epigenetic modifications Bohovych & Khalimonchuk, Front. Cell Dev. Biol. (2016)

26 Mitochondrion to nucleus communication - UPRmt Upon stress, AFTS-1/ATF5 localizes to the nucleus and initiates UPRmt-like response No stress Stress Phsp-6::GFP Ed Germany (unpublished) Bohovych & Khalimonchuk, Front. Cell Dev. Biol. (2016)

27 Mitochondrion to nucleus stress communication - ROS Destabilization of the respiratory supercomplexes in Oma1-deficient cells impinges on TORC1-Rim15-Msn2/4 signaling axis Bohovych & Khalimonchuk, Front. Cell Dev. Biol. (2016) Bohovych et al., Mol. Cell. Biol. (2016)

28 Take home messages Sustaining normal mitochondrial function is critical for cellular welfare Several aspects of mitochondrial function may turn into disaster routes and need to be tightly controlled by mitochondrial quality control mechanisms Mitochondrial quality control is a multi-faceted and hierarchal set of interdependent mechanisms at both molecular and organellar levels Mitochondrial proteases play key roles in the majority of MQC mechanisms Mitochondria effectively communicate with nucleus and other organelles via several mechanisms which involve MQC proteases Under certain conditions, transient mitochondria-derived ROS can be amplified and act as hormetic-like signals interfering with key cellular signaling pathways