Mitochondrial dynamics, Mitophagy and Autophagy
Mitochondrial import protein pathway
Autophagy pathway
Legend
Mitochondrial import pathway
Mitochondrial fusion & fission pathways
Mitophagy pathway
The majority of mitochondrial membrane proteins are encoded by the nuclear genome and transported within the
organelle via the Translocase of Outer Membrane (TOM) complex. Most mitochondrial proteins are synthesized as
cytosolic precursors containing uptake peptide signals. Sorting and assembly of proteins is assisted by specific
machinery (SAM complex) localized on the Outer Mitochondrial Membrane (OMM). The insertion of proteins into the
inner membrane (IM) is mediated by the carrier Translocase of the IM (TIM ), the TIM22 complex. Matrix-targeted
and inner membrane-sorted pre-proteins with cleavable N-terminal presequences, are instead directed to the TIM23
complex. Translocation of pre-protein domains across the IM requires the ATP-driven Presequence translocaseAssociated Motor (PAM). A small number of the IM proteins are encoded by the mitochondrial DNA and for these,
Oxa1 is the main insertase which, together with Mdm38 and Mba1, binds ribosomes and inserts the proteins into the
IM. Mitochondrial intermembrane space (IMS) proteins with cysteine motifs require the Machinery for Import and
Assembly (MIA) based in the mitochondrial IMS.
Mitochondrial fusion and fission dynamics
Mitochondria exist in a dynamic network within living cells, thus undergoing continuous events of fusion and fission.
This depends on the action of three large GTPases: mitofusins (Mfn1, Mfn2) mediating membrane fusion on the OM
level and Opa1 which is essential for the fusion of the inner membranes of the organelle. Mitochondrial fission
requires local organization of Fis1 and recruitment of the GTPase DRP1 for assembly of the fission machinery that
subsequently leads to membrane scission.
Mitochondrial autophagy
This is the process of selective removal of damaged mitochondria by autophagosomes and subsequent catabolism
by lysosomes. Following depolarization of the mitochondrial membrane potential (DYm), the PTEN-induced putative
kinase 1 (PINK1) is accumulated in the defective mitochondria triggering the recruitment of the E3 ubiquitin protein
ligase (Parkin). Once on the mitochondria, Parkin promotes the ubiquitination of mitochondrial substrates embedded
in the OMM such as the mitofusin Mitochondrial Assembly Regulatory Factor (MARF), mitofusin 1 and 2 (Mfn1, 2)
and the Voltage-Dependent Anion-Channel 1 (VDAC1). Subsequent to this, p62/SQSTM1/sequestosome-1 (referred
to as p62), is also recruited to mitochondria, binding the Parkin-ubiquitinated substrates and linking these to
Microtubule-associated protein Autophagy marker Light Chain 3 (LC3) for the autophagic degradation. LC3 binds the
autophagosome membrane together with AuTophaGy proteins 5-12 (Atg5-Atg12) complex and mitochondria
engulfed after elongation of the isolation membrane. Soon after autophagosomes formation, its outer membrane
fuses with lysosomes to form the autolysosomes in which the lysosomal hydrolases (cathepsins and lipases)
degrade the intra-autophagosomal content. Cathepsin also degrades LC3 on the intra-autophagosomal surface.
Autophagy (or autophagocytosis) is the basic catabolic mechanism that involves cell degradation of unnecessary
or dysfunctional cellular components through the lysosomal machinery. This can be induced by both internal and
external stimuli. Autophagy is inhibited under nutrient-rich conditions and therefore stimulated by starvation. A key
regulator or gatekeeper of autophagic induction is mammalian Target of Rapamycin (Tor/mTOR). With the exception
of inadequate nutrients or in the presence of mTOR inhibitors e.g. Rapamycin or mTOR, autophagy is induced. More
than 30 AuTophaGy (ATG)-related proteins form the core machinery of the autophagy pathway. Formation of the
autophagosome is dependent on the formation of 2 complexes - ATG6 (Beclin1) which interacts with the Class III
P13K proteins complexes with ATG14, the second complex involves ATG12, ATG16, ATG5 and ATG7. This complex
is critical for the recruitment of ATG8 (LC3). Upon induction of autophagy, cytosolic LC3-I (ATG8) is cleaved and
lipidated to form LC3-II. LC3 is a marker for the autophagosome membrane. Fusion between the autophagosome
and the lysosyme and subsequent breakdown of the autophagic vesicle is less well defined, though there is an
essential role for the LAMP2 protein in this process.
Discover more at abcam.com/mitochondrialdynamics
Copyright © 2012 Abcam, All Rights Reserved. The Abcam logo is a registered trademark.
All information / detail is correct at time of going to print.
This poster was made in collaboration with Michelangelo Campanella, Department of Comprarative Biomedical Sciences, The Royal Veterinary College, University of London.
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Autophagy