Graduate Research Course · Cell Biology Track
Mitochondria — Biophysics, Biochemistry & Medicine
The eukaryotic cell’s endosymbiotic power plant — from 1.5-billion-year-old α-proteobacterial origin to in vitro mitochondrial transplantation and three-parent IVF.
About This Course
A human body contains ~10 quadrillionmitochondria — perhaps the most numerous “entity” in your body aside from individual protein molecules. Each is a walled miniature chemical plant running ~10 000 ATP synthase rotations per seconddriven by a 200 mV proton motive force across a two-membrane compartment whose ancestor was a free-living α-proteobacteriumengulfed ~1.5 billion years ago (Margulis 1967 endosymbiosis).
This nine-module course covers the endosymbiotic origin, the inner-membrane cristae architecture, the 16 569 bp human mtDNA + heteroplasmy, the structural biochemistry of Complexes I-IV (cryo-EM), the Boyer F0F1rotary motor, reactive-oxygen-species biology, mitochondrial dynamics + mitophagy, mitochondrial disease (MELAS, Leigh, LHON, Warburg), and the emerging therapeutic frontier of three-parent IVF + mitochondrial transplantation.
Cross-links: Cell Physiology / ATP Synthase,Electron Transport,Biochemistry,Disease & New Approaches,Molecular Biology,Cytoskeleton.
Key Equations
Proton Motive Force
\( \Delta p = \Delta\psi - \frac{RT}{F}\Delta\mathrm{pH} \)
Free Energy of ATP Synthesis
\( \Delta G_{ATP} = \Delta G^{\circ'} + RT\ln\frac{[\text{ATP}]}{[\text{ADP}][\mathrm{P_i}]} \)
P/O Ratio
\( \text{P/O} = \frac{\text{H}^+/e^-}{\text{H}^+/\text{ATP}} \)
ATP Synthase Torque
\( \tau = F \cdot r \approx 50\,\text{pN}\cdot\text{nm} \)
Heteroplasmy Drift
\( \text{Var}(f) = f_0(1-f_0)\bigl(1-e^{-t/N_e}\bigr) \)
ROS Equilibrium (superoxide)
\( [\mathrm{O}_2^{-\cdot}] = \frac{k_{gen}}{k_{SOD}[\text{SOD}]} \)
Nine Modules
M0
Origin & Endosymbiosis
Margulis 1967 endosymbiotic theory, α-proteobacterial ancestor (Rickettsia-like), Gray 1999 molecular evidence, Roger 2017 Asgard/eukaryogenesis, hydrogenosomes, mitosomes.
M1
Ultrastructure & Membranes
Inner (IMM) + outer (OMM) membrane architecture, cristae geometry, MICOS complex (Mitofilin/MIC60), contact sites (MAMs), TOM/TIM import, Palade 1952 EM discovery.
M2
Mitochondrial Genome (mtDNA)
16 569 bp human circular, 37 genes (13 OxPhos + 22 tRNA + 2 rRNA), maternal inheritance, heteroplasmy, mitochondrial Eve 200 kya, mtDNA mutation rate 10× nDNA.
M3
Oxidative Phosphorylation
Complexes I-IV cryo-EM structures, Mitchell 1961 chemiosmotic hypothesis, Q-cycle at Complex III, cytochrome c mobile carrier, PMF Δp = Δψ − (RT/F)ΔpH ~200 mV.
M4
ATP Synthesis (F0F1)
Boyer 1997 binding-change Nobel, Walker 1994 F1 atomic structure, Yasuda 1998 single-molecule rotation, 3 ATP per revolution, ~50 pN·nm torque, ~30% net efficiency.
M5
ROS & Oxidative Stress
Superoxide from Complex I/III backslip, hydrogen peroxide, SOD2 manganese dismutase, catalase, GPX1 glutathione cycle, Ristow 2009 mitohormesis, Harman 1956 free-radical aging.
M6
Dynamics: Fusion & Fission
Mitofusin 1/2 (Mfn1/2) outer-membrane fusion, OPA1 inner, Drp1 + Fis1 fission, mitophagy via PINK1/Parkin pathway, mitochondrial networks, Nakamura 2022 cryo-EM.
M7
Mitochondria in Disease
Leigh syndrome, MELAS (3243A→G tRNA-Leu), LHON optic neuropathy, Kearns-Sayre, Parkinson's (Parkin/PINK1 loss), cancer Warburg reversal, aging as mitochondrial decline.
M8
Therapies & Transplantation
3-parent IVF (UK 2015 approved, pronuclear/spindle transfer), MitoQ/SkQ1 antioxidants, SS-31 peptide, mitochondrial transplantation (McCully 2017 cardiac), gene therapy AAV.
Key References
- [1] Margulis, L. (1967). On the origin of mitosing cells. J. Theor. Biol., 14, 225–274.
- [2] Mitchell, P. (1961). Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature, 191, 144–148.
- [3] Boyer, P. D. (1997). The ATP synthase — a splendid molecular machine. Annu. Rev. Biochem., 66, 717–749.
- [4] Yasuda, R. et al. (1998). F1-ATPase is a highly efficient molecular motor that rotates with discrete 120° steps. Cell, 93, 1117–1124.
- [5] Wallace, D. C. (2005). A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer. Annu. Rev. Genet., 39, 359–407.
- [6] Friedman, J. R. & Nunnari, J. (2014). Mitochondrial form and function. Nature, 505, 335–343.
- [7] Ristow, M. & Schmeisser, K. (2014). Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species. Dose-Response, 12, 288–341.
- [8] McCully, J. D. et al. (2017). Mitochondrial transplantation for therapeutic use. Clin. Transl. Med., 6, 13.