Mitochondria

Summary of common mechanisms of neurodegeneration

• Excitotoxicity

• Autophagy-lysosome pathway

• Protein quality control:chaperone, proteasome

• Mitochondrial metabolism, homeostasis, quality control

• Protein misfolding and aggregation

5 functions of the mitochondria

• Production of NADH and energy

• Production of metabolites

• Ca++- storage organelles (ER)

• Production of reactive oxygen species

• Initiators of apoptotic cascade

Mitochondrial fusion

• Mitofusin (Man) 1 and 2

• Optic atrophy (OPA)1

• Stimulated by energy demand and stress

• Complementation- fuse to supply mission proteins

Mitochondrial fission

• Fis 1

• Dynamin-related protein (Drp)1

• Endophilin B1

What happens when there is no fusion?

Mitochondria look like dots not rods

What happens when there is no fission

Start abnormally fusing together

Role of dynamics

• Fragmentation recruits mitochondria to cellular compartments in need of ATP

• Fusion could be a coping mechanism

• Increased fusion inhibits apoptosis

• Apoptosis is associated with fission

What is the early event in AD, PD, ALS, HD

Impaired mitochondrial function

Other mechanisms in neurodegeneration

• Altered mitophagy- accumulation of dysfunctional, ROS

• Impaired production og ATP

• Mitochondrial fission

What are the three therapeutic strategies

• Compounds that inhibit mitochondrial fission

• Bioenergetic compounds

• Mitochondria-trageted antioxidants

What drugs inhibits mitochondrial fission

Mdivi-1

Cytoprotection of Mdivi-1

• Dependent on Drp1

• Inhibits Bax/Bak- mediated apoptosis

• Activates AKT and ERk1/2 pathways

• Reduces ROS

Cytotoxic effects of Mdivi-1

• Independent of Drp1

• Impairs DNA replication

• Induces G2/M cell cycle arrest

Bioenergetic: creatine

• Crutial energy reservoir for ATP

• creatine/phosphocreatine system

• Role in maintaining energy balance in brain and muscles

• Buffering ATP levels

• miCK, cCK

Creatine/phosphocreatine shuttle system

Saved as mito pic

How is creatine neuroprotective

• Increased availability of cytosolic ATP

• Inhibition of the mitochondrial permeability transition pore

• Little is taken up into the brain so trials are being stopped

Bioenergetic: coenzyme Q

• Cofactor of the ETC (accepts e-)

• Potent anti-oxidant in the inner mito membrane

• Anti-apoptotic: block BAX association and inhibits mitochondrial permeability transition pore

• Can’t cross BBB

Idebenone

Synthetic more soluble analogue of COenzymeQ10

Effective in AD not in HD

Only some reaches the mitochondria

MitoQ

Add triphenyl-phosphonium group to coenzyme Q

Rapidly reduced to the active quinoa form by respiratory system

Inserts into mid membrane and protects lipids and proteins from oxidative damage

TPP conjugated antioxidants exists too

What is mitt effective in

Fibromyalgia and MS chronic fatigue

Szeto-schiller peptide (SS-31)

• Structural motif- 4 aromatic, 4 basic (aromatic-cationic peptides)

• Free penetrate cells and accumulate in mitochondria

• Tyrosine reside scavenges oxyradicals

SS-31 in trials

Can cross BBB

For cardio protection after heart attack