Mitochondrial Function

Mitochondrial Structure - Powerhouse Blueprint

• "Powerhouse": Primary site of ATP synthesis (oxidative phosphorylation).
• Double Membrane:
  • Outer Membrane (OMM): Smooth, permeable (due to porins).
  • Inner Membrane (IMM): Folded into cristae (↑ surface area). Houses ETC complexes & ATP synthase.

    ⭐ Cardiolipin in IMM makes it highly impermeable to ions, essential for maintaining the proton gradient.

• Intermembrane Space (IMS): Located between OMM & IMM. Contains cytochrome c (apoptosis).
• Matrix: Innermost space. Contains mtDNA, ribosomes, enzymes for TCA cycle, fatty acid oxidation.

​

Electron Transport Chain - Electron Hustle

• Location: Inner mitochondrial membrane (IMM).
• Goal: Oxidize NADH & FADH₂; transfer electrons to $O_2$; pump $H^+$ from matrix to intermembrane space (IMS), creating proton-motive force.
• Components:
  • Complex I (NADH dehydrogenase): NADH → CoQ. Pumps 4$H^+$.
  • Complex II (Succinate dehydrogenase): FADH₂ → CoQ. No $H^+$ pumping.
  • Coenzyme Q (Ubiquinone): Mobile electron carrier.
  • Complex III (Cytochrome bc₁ complex): CoQ → Cytochrome c. Pumps 4$H^+$.
  • Cytochrome c: Mobile electron carrier.
  • Complex IV (Cytochrome c oxidase): Cytochrome c → $O_2$. Pumps 2$H^+$. $O_2$ reduced to $H_2O$.
• Electron Flow:

• 📌 ETC Inhibitors: RotenONE (Complex I), AnAAmycin (Complex III), CO/CN⁻/H₂S IDE (Complex IV).

⭐ Cyanide (CN⁻) and Carbon Monoxide (CO) are potent inhibitors of Complex IV (Cytochrome c oxidase), halting electron transport and ATP synthesis, leading to rapid cellular hypoxia.

Oxidative Phosphorylation - Energy Mint

• Mechanism: ATP synthesis fueled by energy from electron transfer (NADH/FADH₂ → O₂) via ETC on Inner Mitochondrial Membrane (IMM).
• Chemiosmosis (Mitchell): ETC pumps H⁺ (matrix → Intermembrane Space/IMS), creating Proton-Motive Force (PMF; an electrochemical gradient).
• ATP Synthase (Complex V; F₀F₁ ATPase):
  • F₀ (IMM): Proton channel for H⁺ re-entry to matrix.
  • F₁ (matrix): Catalytic sites; $ADP + P_i + H^+{matrix} \rightarrow ATP + H_2O + H^+{IMS}$.
• P/O Ratios:
  • NADH: ~2.5 ATP (enters Complex I).
  • FADH₂: ~1.5 ATP (enters Complex II).
• ⭐ > Uncouplers (e.g., 2,4-DNP, aspirin overdose) dissipate proton gradient, ↑O₂ consumption, ↓ATP synthesis, produce heat. (Thermogenin is a natural uncoupler).

Mito Dysfunction & Roles - When Power Fails

• Dysfunction: Causes & Features
  • Genetic: mtDNA mutations (e.g., MELAS, LHON, MERRF); nuclear DNA gene defects.
  • Acquired: Ischemia/reperfusion, toxins (CN⁻, CO), drugs (zidovudine), ↑ROS.
  • Results in impaired oxidative phosphorylation (OXPHOS).
• Consequences of Failure
  • ↓ATP synthesis: Energy crisis, particularly in high-demand tissues (brain, heart, muscle).
  • ↑ROS production: Oxidative stress, lipid peroxidation, further mtDNA damage.
  • Apoptosis initiation: Release of cytochrome c, activating caspases.
• Beyond Energy: Critical Roles
  • $Ca^{2+}$ homeostasis: Sequesters and releases $Ca^{2+}$, shaping signals.
  • Metabolic pathways: Heme synthesis, steroid hormone synthesis (initial steps).
  • Thermoregulation: Non-shivering thermogenesis via UCP1 in brown adipose tissue.

⭐ Mitochondrial DNA (mtDNA) is exclusively maternally inherited and has a high mutation rate. oka

High‑Yield Points - ⚡ Biggest Takeaways

• Mitochondria: Powerhouses; main site of ATP synthesis via oxidative phosphorylation.
• Electron Transport Chain (ETC): Located on inner mitochondrial membrane (IMM).
• Chemiosmosis: Proton gradient across IMM drives ATP synthase (Complex V).
• Uncoupling proteins (e.g., thermogenin/UCP1) dissipate proton gradient, generating heat.
• Mitochondrial DNA (mtDNA): Maternally inherited, circular; codes for some ETC components.
• ETC Inhibitors: Rotenone (C-I), Antimycin A (C-III), CN-/CO (C-IV), Oligomycin (ATP synthase).
• Role in apoptosis (cytochrome c release) and Ca2+ homeostasis.