Despite the presence of the mitochondrial genome in the cell, only few mitochondrial proteins are encoded by the mitochondria itself. The vast majority are encoded in the nucleus and consequently synthesized (transcribed) in the cytosol as precursor proteins containing mitochondrial targeting elements that target them to the mitochondria.
Mitochondrial targeting elements exist as single or multiple units scattered along the length of the precursor and vary in terms of sequence, structure and location.
The most common or "classical" presequence is an N-terminal stretch of 15–55 amino acids which is cleaved upon import.
It is assumed that mitochondrial protein import primarily occurs post-translationally. This necessitates the requirement for cytosolic chaperones to maintain the precursor proteins in their unfolded and import-ready states.
The mitochondria contain four compartments:
Translocase of the Outer Membrane (TOM)
This complex on the outermost barrier serves two purposes:
Translocase of the Inner Membrane Complex (TIM)
Depending on target elements present on the precursor, there are two possible pathways for it to follow that involve Tim22 or Tim23:
Tim22 plays a role in the import of the IMM metabolite carrier proteins which do not contain an obvious targeting sequence. Their hydrophobic precursors are maintained in unfolded state in the cytosol by chaperones and are delivered to the receptor Tom70 on the mitochondrial surface. Once past the TOM complex, they interact with the Tim9–Tim10 chaperone complex on the intermembrane space which facilitates their the journey through the aqueous environment of the intermembrane space.
After passing through the IMS, they dock onto the TIM22 complex with the help of Tim9–Tim10–Tim12 complex and pass through the channel that Tim22 molecules form.
The insertion of the precursors into the inner mitochondrial membrane takes places in a membrane potential-dependent manner. Ultimately, the carriers assemble into functional dimers.
The presequence import pathway to the mitochondrial matrix (and IMM)The Tim23 complex functions in the import of proteins containing a presequence targeted for the matrix. Tim23 is also important in the import of IMM proteins that span the membrane in a single-helix conformation.
The Tim23 protein complex is composed of three core proteins:
Translocation of precursor proteins into the mitochondrial matrix requires additional factors:
However, precursors that contain a hydrophobic "sorting signal" downstream of the presequence (hydrophobic precursors) are re-targeted for integration into the inner mitochondrial membrane.
Preprotein assembly and machinery complex (PAM)
Mitochondrial targeting elements exist as single or multiple units scattered along the length of the precursor and vary in terms of sequence, structure and location.
The most common or "classical" presequence is an N-terminal stretch of 15–55 amino acids which is cleaved upon import.
It is assumed that mitochondrial protein import primarily occurs post-translationally. This necessitates the requirement for cytosolic chaperones to maintain the precursor proteins in their unfolded and import-ready states.
The mitochondria contain four compartments:
- outer mitochondrial membrane (OMM)
- intermembrane space (IMS)
- inner mitochondrial membrane (IMM)
- matrix
Translocase of the Outer Membrane (TOM)
This complex on the outermost barrier serves two purposes:
- contains receptors that present docking sites for precursor proteins
- provides a safe channel for the translocation of precursor proteins across the outer mitochondrial membrane
- Tom40 - a β-barrel subunit which forms the central pore of the complex
- Tom22 - serves as the central receptor for import
- Tom5 - assists with the transfer of precursors
- Tom6 - stabilizes the TOM complex
- Tom7 - assists TOM dissociation
- Tom20 and 7. Tom70 - serve as peripheral receptors
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| Mitochondrial Protein Import Biochimica et Biophysica Acta 1808 (2011) 1002-1011 |
Depending on target elements present on the precursor, there are two possible pathways for it to follow that involve Tim22 or Tim23:
- insertion into the inner mitochondrial membrane (Tim22, Tim23 - via carrier import and presequence pathways)
- import into the mitochondrial matrix (Tim23 - via presequence pathway)
Tim22 plays a role in the import of the IMM metabolite carrier proteins which do not contain an obvious targeting sequence. Their hydrophobic precursors are maintained in unfolded state in the cytosol by chaperones and are delivered to the receptor Tom70 on the mitochondrial surface. Once past the TOM complex, they interact with the Tim9–Tim10 chaperone complex on the intermembrane space which facilitates their the journey through the aqueous environment of the intermembrane space.
After passing through the IMS, they dock onto the TIM22 complex with the help of Tim9–Tim10–Tim12 complex and pass through the channel that Tim22 molecules form.
The insertion of the precursors into the inner mitochondrial membrane takes places in a membrane potential-dependent manner. Ultimately, the carriers assemble into functional dimers.
The presequence import pathway to the mitochondrial matrix (and IMM)The Tim23 complex functions in the import of proteins containing a presequence targeted for the matrix. Tim23 is also important in the import of IMM proteins that span the membrane in a single-helix conformation.
The Tim23 protein complex is composed of three core proteins:
- Tim23 - this is the central channel protein
- Tim50 - cooperates with TOM complex and acts as a receptor for incoming cargo of precursors
- Tim17 - recruits the PAM complex
- Tim21* - involved in interactions with TOM complex and also mediates association of the translocase to the components of respiratory chain complexes III and IV.
Translocation of precursor proteins into the mitochondrial matrix requires additional factors:
- the membrane potential
- presequence translocase-associated motor (PAM). Association of PAM with TIM23 gives rise to the TIM23MOTOR form of the complex.
However, precursors that contain a hydrophobic "sorting signal" downstream of the presequence (hydrophobic precursors) are re-targeted for integration into the inner mitochondrial membrane.
Preprotein assembly and machinery complex (PAM)
PAM consists of:
Sorting and Assembly Machinery (SAM)
As the name implies, this complex serves to assemble outer mitochondrial membrane proteins that possess β-barrel confirmations and play a vital role in its function.
- mtHsp70 - mitochondrial Hsp70
- Mge1 - nucleotide exchange factor
- Tim44 - links mtHsp70 to the TIM23 complex
- Pam16/17/18 - additional co-chaperones
Sorting and Assembly Machinery (SAM)
As the name implies, this complex serves to assemble outer mitochondrial membrane proteins that possess β-barrel confirmations and play a vital role in its function.
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