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WEEK 3:Mitochondrial adaptation and Degeneration, upon activation bind to…

- - - - using biochemical assays Cytochrome C and Succinate oxidase: after exercise there was more MT than before exercise. this indicates using Biochemical assays, the enxymes activates are elevated following exercise which leads to Increase MT activty.
    - - using mt DNA as a marker for MT biogenesis.
    - - Caloric restriction
        
        you get more mt through caloric restriction
      - Hypoxia in neurons
        
        reducing the amount of O2 is a good stimulus for mt biogenesis. there is more mt biogenesis so that you can use the aviavle oxygen better.
      - Cold exposure in muscles
        
        graphs show that as it gets colder, there is more mt biogensis.
      - Question: does mitochondrial prodction work on a negative feed back loop? can we infer that stress induces MT biogenesisl.
    - - MT biogenesis occurs in metabolically active tissues after exercise e.g the heart, liver, the brain
        
        Exercise drives: mt biogenesis, MT fusion, drives an increase density of mt christi (in type 1 fibres)
        
        = Exercise drives an increased density of mt christis (located in the inner mt memebrnae) in endurance trained athletes the cysae denstiy in type 1 fibres is increased= good adaptation as it increase the surface area of the inner mt membrane (the home of the electron transport chain). more surface area= cram in more electron transport chain= generate more ATP production= more energy
  - - - Mitofusin's the most important protiens that mediate the fusion of two mitochondria. they are also GTPases(enzymes that can catalyse the hydrolysis of GTP to GDP) mfn1 and mfn2 are the two mitofusin that mediate. (key notes: the GTP hydrolysis stimulates the fusion of the outer membrane of the mitochondria)
        
        Each mitochondria contain a mitofusin protien. which form dimers across opposing outer mitochondrial membranes.
        
        Fussion of the mitochondrial OUTER MEMBRANE GTP molecules binds to the GTPASe regions of the mitofusin protein= proteins regidly attach to one another and undergo a conformational change.= the two opposite membranes into closer proximity.
        
        the mitofusins hydrolyses the GTP= a GTP power stroke( the hydrolysis of GTP releases loads of energy that cases the proteins to move and due to the nature of the confirmation of the protiens)= the two mitochondrial memebrane come into contact to one another.= casues the fusion of the two outer mitrochondrial membranes.
      - Fusion of the mitochondrial INNER MEMBRANE
        
        Optic atrophy 1 (OPA1) drives inner membrane fusion (through GTPase function)
        
        OPA1 is recruited to the inner mt membrane after the mitofsins have been recrutied. OPA1 another GTPase that drives inner membrane fussion,
      - Exercise as a model (as it is an important stimulus of mt adaptation)
        
        In skeleltal muscle aerobic training elongates the mitochondrial reticulum (which is probably driven by the increase in mitofusin expression following exercise). Exercise (in an acute bout) also increase the expression of mitofusin 1 &2.
      - What is the point of fusion: fussion allows functional mt to complement dysfunctional mt by diffusion and sharing f components between organelles( thus sharing the worklode/stress between mts.) if dyfunction is bad, fission occurs leading to mitophagy
    - - Key note: mitochondria form contact points with the endoplasmic rectium these contact points are called Mitochondria associated ER membranes(MAMS) they are cruital for the process of fission
      - when two mt what to break apart one of the membranes of the
        ER will wrap around a mt and constrict it (bringing the outer membranes closer together)
        
        Drp1( a GTPase) gets recruited to the site of the mt where is it being restricted. Drp1 binds adaptor protien Mff and oligermises ( forms a crowd?)
        
        Drp1 hydrolyses GTP and causes further constriction of the mt
        
        Dnm2 (dynamin 2 ) is a scission factor. this protein cuts the mt so that it breaks in half.
      - Key regulator of Mt fission: Drp1 as when this is knocked out from a cell then mt fission does not occur
      - Exercise is stimulus fir mt fission but fission is laos important in the cell cylce (G2 phase, and in the m phase you want mt in the new cells)
- - - - AMPK
        
        Phosphorylates
        
        PGC1(alpha) Master regulator of Mt biogenesis
        
        upon phosphorylation, it translocates into the nucleus where it then binds to the Transcription factors and actives them which allows them to bind to the promotor region of DNA where it can be effective as a transcription factor.
        
        NRF1 key regulator of mtbiogensis
        
        NRF2 key regulator of mtbiogenesis
        
        PGC1-A is a transcriptional co activator( it binds to transcription factors and helps TF to work more effectivity.
        
        Puigserver et al 1998 .
        
        PGC1-A was over-expressed in (adipocytes) fat cells, they saw that all other mt protiens COX-11, COXIV, UCP-1, ATP synthase( mitochondrial protiens) mt DNA they all increased.
        = proves the PGC-1 is the master regulator of mt biogenesis
  - - - TOM( translocate of the outer memebrane, livers on the memebrane lets stuff in and out)
      - PINK1 = a kinase
    - - Study shows that: parkin is present in Mitochondria and with exercise you get more parkin in the mitochondria. The downstream effect of more parkin in the mitochondria is the amount of mitochondrial proteins that are ubiqinated (with exerise this increases)