Skip to content
Login Register

#mitochondrial protein import

3 public questions tagged with this topic.

Protein Sorting and Trafficking

What is the function of Hsp70 chaperones during mitochondrial protein import?

Cytosolic steps preceding mitochondrial import require chaperoning maintain precursors loosely folded translocation competent capable threading narrow TOM 20 angstrom channel. Nascent chains emerging ribosome contain hydrophobic segments aggregation-prone aqueous cytosol. Cytosolic Hsp70 family mainly Ssa1-4 yeast and HSPA1A HSPA8 mammals with co-chaperones Ydj1 Sis1 J-domain stimulating ATPase nucleotide exchange Sse1 Bag family bind exposed hydrophobic patches substrate binding domain ATP-dependent holdase preventing misfolding self-association aggregation delivering precursors Tom70 receptor tetratricopeptide clamp binding Hsp70 EEVD motif. Cycling ATP-bound low affinity ADP-bound high affinity regulated ATP hydrolysis tightens grip NEF-triggered ADP release loosens. Within IMS matrix distinct Hsp70 paralogs Tim14-16 mtHsp70 provide directional pulling motor. Hsp70 does not directly degrade misfolded precursors though may recruit CHIP E3 triaging aggregates proteasome does not block TOM channel opening does not generate vesicles mitochondrial transport occurs soluble chaperoned diffusion. Depletion cytosolic Hsp70 cytosolic precursor foci aggregates reduced import illustrating protective role essential mitochondrial biogenesis preventing proteotoxic stress and maintaining proteostasis cellular health and viability.

Ref: Young et al., Cell 2003: Cytosolic Hsp70 chaperones mitochondrial precursor aggregation prevention.

View Details
Protein Sorting and Trafficking

The TIM23 complex is primarily involved in:

Inner mitochondrial membrane protein import presequence pathway uses TIM23 complex distinct carrier TIM22. After crossing outer membrane Tom40 pore proteins bearing N-terminal positively charged amphipathic presequence arginine lysine hydroxylated recognized via Tim50 IMS receptor presequence groove interacting Tim23 channel. TIM23 complex comprises Tim23 voltage-gated aqueous channel C-terminal domain four transmembrane helices regulated Tim50, Tim17 paralog stabilizing pore, Tim21 bridging respiratory chain, Mgr2 gating Tim50. Driving forces two components: membrane potential Delta psi negative 180 mV inside electrostatically attracting positive presequence electrophoresis, ATP-dependent presequence associated motor PAM containing matrix Hsp70 mtHsp70 anchored Tim44 co-chaperone Pam16-Pam18 regulating ATPase pulling polypetide Brownian ratchet into matrix. Matrix-targeted proteins processed cleaved mitochondrial processing peptidase MPP removing targeting sequence. Inner membrane proteins lateral release via stop-transfer hydrophobic sorting or conservative sorting via Oxa1 after matrix import. TIM23 does not transport lipids recycle proteins mediate degradation lipid handled ERMES proteolysis LON m-AAA. Essential respiration biogenesis TIM23 mutations multi-system disease lactic acidosis mitochondrial encephalomyopathy and developmental delay.

Ref: Neupert & Herrmann, Annu Rev Biochem 2007: TIM23 imports proteins into mitochondrial matrix via motor.

View Details
Protein Sorting and Trafficking

Which complex is responsible for mitochondrial protein import into the outer membrane?

Mitochondrial proteome exceeds 1000 proteins but mitochondrial genome encodes only 13 hydrophobic subunits humans requiring massive import nuclear encoded precursors cytosolic ribosomes. Entry gateway TOM complex translocase outer membrane central hub 400-500 kDa. Core beta-barrel channel Tom40 19 beta strands hydrophilic pore about 20 angstrom unfolded polypeptide passage. Associated receptors provide specificity: Tom20 tetratricopeptide clamps amphipathic presequence hydrophobic face, Tom70 clamp binds internal hydrophobic signals carriers via Hsp70/Hsp90 chaperone docking, Tom22 central organizer acidic cytosolic intermembrane space domains. Small subunits Tom5 Tom6 Tom7 regulate assembly dynamics. Precursors engage receptor transfer Tom22 then traverse Tom40 aqueous channel intermembrane space where small Tim chaperones Tim9-Tim10 guide downstream translocases: TIM23 for presequence matrix proteins TIM22 for polytopic carriers SAM for outer beta-barrels MIA for oxidative folding IMS proteins. TIM23 TIM22 OXA reside inner membrane performing inner steps not outer; OXA inserts mitochondrially encoded proteins. TOM unique outer entry gate conserved yeast human essential viability and biogenesis and organelle maintenance.

Ref: Wiedemann & Pfanner, Annu Rev Biochem 2017: TOM complex outer membrane import machinery.

View Details