BIOL 201 Lecture Notes - Lecture 6: Lysosome, Pink1, Ubiquitin Ligase
If mitochondria break down in certain tissue, has impact on that tissue
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Mutations in mitochondria cause disease in 1/5000 live birth (many diseases, affects every organ of
the body)
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Tissue-specific gene programs that control their development
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Mutation that does not cause complete mitochondrial breakdown, but may cause specific
morphology change that affects function in specific tissue
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Mitochondria morphology varies in different tissues
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Undergo fusion and fission constantly
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Do not just diffuse, are actively transported
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Why do these mitochondria undergo fusion and fission?
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Form interconnected tubular network
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Cells exhibit fragmentation of their mitochondria during low generation of ATP via oxidative
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Phosphorylation
During increased mitochondrial generation of ATP via oxidative phosphorylation cells exhibit
an extensive network of fused mitochondria
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Mitochondrial structure and function can change in response to the metabolic state of the cells.
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MFN1 (mitofusin 1), MFN2 (mitofusin 2), OPA1, DRP1
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Fusion and fission mediated by set of four evolutionarily conserved GTP-hydrolyzing (GTPase)
enzymes of the dynamin family:
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dimerizing and undergoing conformational change to bring membranes in close
proximity
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The integral membrane proteins MFN1 and MFN2 (MFN1/2) mediate outer mitochondrial
membrane (OMM) fusion
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Undergo similar conformational change to bring inner membranes together
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fusion of the inner mitochondrial membranes (IMM) mediated by the integral membrane
protein OPA1
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The matrix and inner membrane space (IMS) remain distinct
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When individual mitochondria fuse, each of the two membranes fuses (inner with inner, and
outer with outer)
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Fusion is a 2 step process
oligomerizes into a polymer that forms constricting band around mitochondria
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DRP1 is recruited to a constricted site on the surface of a mitochondrion, where DRP1 polymers sever the membrane
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Fission uses a GTPase to squeeze mitochondria apart
LOF mutation of one protein = overexpression of the other
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DRP mutant has one giant interconnected mitochondrial network
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MFN mutant causes mitochondrial fragmentation
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Fusion and fission apparatuses are constantly active, WT cell is in active
steady state with both processes occurring simultaneously
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Overexpression of DRP-1 causes same phenotype as MFN-null
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Must be some motivation for continual activity
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Fission and fusion mutants have opposite phenotypes
Damage in form of Reactive Oxygen Species are a by-product of metabolism
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Superoxide = Reduced bimolecular oxygen from stray electron reduction
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Form of intracellular pollution
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Continuous fusion and fission allows for management of pollution
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Mitochondria accumulate damage to their DNA and protein contents
Red and green dye will actually mix when cells come together due to cycling of
dyes through fusion and fission network
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Red mito does not contain mtDNA necessary for production of new non-
defective protein
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After fusion and fission, mitochondria now contains mtDNA to make
functional protein and mutant protein becomes diluted
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Fission and fusion enable mitochondrial rescue
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fusion helps to maintain a relatively homogeneous population of mitochondria
within a cell.
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also plays a role in the proper localization of mitochondria within cells,
maintaining the proper morphology and cristal organization
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Should some subset of individual mitochondria suffer deleterious modification
or loss of important components, fusion with other mitochondria would permit
restoration by sharing of those components.
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fission is particularly active when cells divide (G2 and M Phases) the
multiple discrete mitochondria generated are readily distributed evenly
into the daughter cells
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Mitochondria can be transported by motor proteins along cytoskeletal
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Fission promotes the equal segregation of mitochondria into daughter cells
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Fission and fusion promote the mixing of mitochondrial contents
Lecture 6: Mitochondria II
January 21, 2018
8:40 PM
Section 1 Page 1
