Contents

📒 Jafri 2014

Modeling Mitochondrial Function and Its Role in Disease1

Sciwheel

Introduction

  • Mitochondria: ATP generator, signaling, apoptosis
  • Related to diseases

Table1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219577/table/T1/ Table2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219577/table/T2/

ENERGY METABOLISM

TCA cycle

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219577/bin/nihms-638309-f0001.jpg
Tricarboxylic acid cycle

Substrate entry into the TCA cycle

  1. Pyruvate -> AcCoA
  2. FA -> carnitine carrier system
  3. Amino acids -> intermediates

Oxidative phosphorylation

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219577/bin/nihms-638309-f0002.jpg https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219577/bin/nihms-638309-f0003.jpg

  • mitochondrial membrane potential (Δψm): –160 to has –180 mV
  • The proton gradient (ΔpH): 0.1 and 0.5
  • F1F0-ATPase (ATP synthase) H/ATP ratio ≈ 3:1

Substrate transport

  • ATP/ADP translocase (ANT)
  • phosphate carrier (PiC): H2PO4- / OH-
  • malate–aspartate shuttle, the glutamine carrier, and the tricarboxylate carrier protein

Ionic and substrate homeostasis

  • mitochondrial calcium uniporter (MCU)
  • Calcium is buffered in the matrix by binding to proteins, ATP, and ADP
  • mitochondrial sodium–calcium (lithium) exchanger (mNCLX)

MITOCHONDRIAL SIGNALING

ROS signaling

  • ROS: uperoxide (O2–), hydrogen peroxide (H2O2), and peroxynitrite (ONOO–)
  • The amount of mitochondrial superoxide dismutase is 4 times that found in the cytoplasm of heart.
  • H2O2: scavenged by GSH and Trx systems

Calcium signaling

ADP signaling

Apoptosis

MITOCHONDRIA IN DISEASE

Ischemic disease

  • Ischemia: reduced redox state => reperfusion (high ROS production)

Neurodegenerative disease

  • Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS).
  • symptoms are apparent before these proteinopathies are observed (AD)
  • In Parkinson’s disease, Huntington’s disease, and ALS excessive levels of ROS have been observed

MODELS OF MITOCHONDRIAL ENERGY METABOLISM

  • Metabolic oscillations are oscillations in energy metabolism observed during ischemia (not glycolytic oscillations)
    • blocked by antagonists (BZDs) of the mitochondrial inner membrane ion channel (IMAC)
    • Jafri and Kotulska model: phosphate and magnesium
    • Cortassa model: ROS activated (RIRR)
  • OXPHOS: push–pull mechanism
    • Magnus and Keizer model: including calcium dynamics
    • Bertram model: simplified version
    • ECME model: plus cardiac myocyte action potential and calcium dynamics
    • Nguyen–Dudycha–Jafri model: mitochondria in neurons
  • Enzyme reactions: MM (saturation) kinetics https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219577/bin/nihms-638309-f0004.jpg
  • The caveat with this is that the reverse reaction is not well constrained in experimental settings (initial product = 0). Sotheyare often ommited, not compliant to thermodynamics. Often not an issue since reverse reactions are negligible due to large free energy changes.

MODELS OF MITOCHONDRIAL SIGNALING

  • Hong model: cisplatin-induced apoptosis with ER-stress, TNF pathway

CONCLUDING REMARKS

  • there are many opportunities for the development and application of such models and their integration with experimental work

Refrence


  1. Jafri MS, Kumar R. Modeling mitochondrial function and its role in disease. Prog. Mol. Biol. Transl. Sci. 2014;123:103-125. doi:10.1016/B978-0-12-397897-4.00001-2. PMC4219577 ↩︎