Cell Bio Mitochondrion and Aerobic Respiration

modern perspective of mitochondria

dynamic and multifunctional

mitochondria roles beyond ATP

apoptosis, signaling, heat generation

mitochondria

- double membrane organelles in nearly all eukaryotic cells

- generate most of the cell's ATP through aerobic respiration

- evolved from symbiotic bacteria

how is mitochondria distributed in cells?

- location matches energy needs

- supports local ATP supply

- clustered near contractile machinery, synapses, or ion pumps

mitochondria outer membrane

permeable to small molecules

mitochondria inner membrane

impermeable, folded into cristae

mitochondrial compartmentalization

- intermembrane space vs matrix

- compartmentalization enables function

cristae

structural adaptation of mitochondria

- inner membrane folded into cristae

- increases surface area for electron transport and ATP synthesis

- cristae morphology varies with cell type and energy demand

cristae morphology vs energy demand

- cristae density correlates with ATP demand

- more folds = larger surface area for ETC

- tissue-specific variations (heart vs liver)

cardiac muscle mitochondria

- dense cristae

- high mitochondrial density

liver cells

- fewer cristae

- more metabolic versatility

ranking of energy demand (number of mitochondria) of different types of tissues

muscle cells > neurons > liver cells > stomach cells > red blood cells

mitochondria in muscle

- high mitochondrial density, dense cristae

- structure directly supports continuous contraction

- helps muscle repair

mitochondria unique features

semi-autonomous

- own DNA (circular, bacterial-like)

- own ribosomes (70S, similar to bacteria)

- still rely on nuclear-encoded proteins from the cell

- replicate by fission, independent of cell cycle

mitochondrial dynamics

- constantly change via fusion and fission

- regulate mitochondrial shape, number, and function

- balance between repair and quality control

- can sacrifice ATP efficiency for heat production to adapt to needs

overview of metabolite transport

- inner membrane = highly sensitive

- transport proteins required

- regulates metabolic entry

pyruvate

glycolysis product from outside the mitochondria

pyruvate is imported by _____

mitochondrial pyruvate carrier (MPC)

pyruvate import

- once inside, converted to acetyl-CoA by pyruvate dehydrogenase (PDH) or Oxaloacetate by pyruvate carboxylase (PC)

- directly into TCA cycle which generates electron carriers for the ETC->ATP

pyruvate converts to lactate ->

lactic acidosis

lactic acidosis

- pyruvate reduced to lactate by lactate dehydrogenase

- occurs when mitochondria cant oxidize pyruvate

- lactate buildup -> decrease blood pH (lactic acidosis)

fatty acid import pathway through IMM

- fatty acids -> fatty acyl-CoA

- requires ATP investment

- first committed step

- fatty acyl-CoA requires shuttle

carnitine palymitolytransferase I (CPT1): step 1

- CPT1 on outer membrane

- transfers acyl group to carnitine

- produces acyl-carnitine, releasing Coenzyme A

carnitine/acylcarnitine translocase (CAT or CACT): step 2

- located in the inner mitochondrial membrane

- acyl-carnitine imported

- carnitine exported

- translocase=exchanger

carnitine palymitolytransferase II (CPT II): step 3

- CPT II inside matrix

- transfers acyl group back to CoA

- produces fatty acyl-CoA

carnitine deficiency

- defective shuttle -> energy failure

- symptoms: weakness, hypoglycemia

- CPT I/II or translocase defects

citric acid cycle (TCA/Krebs) overview

- central hub of metabolism

- oxidizes acetyl-CoA to CO2

- produces per Acetyl-CoA

- entry into TCA

citric acid cycle (TCA/Krebs) produces per Acetyl-CoA

- 1 GTP/ATP per cycle

- 3 NADH per cycle

- 1 FADH2 per cycle

citric acid cycle (TCA/Krebs) entry into TCA

- glycolysis: 1 glucose (3C) -> 2 pyruvate (3C)

- pyruvate DH: 2 pyruvate -> 2 Acetyl-CoA

-> twice as many products as above per glucose

TCA step 1:

Acetyl-CoA (2C) + oxaloacetate (4C) -> citrate (6C)

TCA step 2:

citrate (6C) isomerized or reorganized to isocitrate (6C)

TCA steps 1 and 2: purpose

- entry and rearrangement

- prepares substrates for oxidation

TCA step 3:

decarboxylation of isocitrate (6C) -> α-ketoglutarate (5C)

TCA step 3: purpose

- produces NADH and CO2

- major control point- energy harvesting reaction

TCA step 4:

decarboxylation of α-ketoglutarate (5C) -> succinyl-CoA (4C)

TCA step 4: purpose

- produces another NADH and a second CO2 is released

- multi-enzyme complex

TCA step 5:

succinyl-CoA -> succinate

TCA step 5: purpose

- produces GTP (or ATP)

- example of substrate-level phosphorylation

- captures energy directly

TCA step 6:

succinate -> fumarate (FADH2)

TCA step 7:

fumarate -> malate (hydration)

TCA step 8:

malate -> oxaloacetate (NADH)

total yields of TCA cycle per acetyl-CoA

- 3 NADH

- 1 FADH2

- 1 GTP/ATP

total yields of TCA cycle

- 2 CO2 released

- key source of reducing power

regulation points of TCA cycle: key enzymes

- citrate synthase

- isocitrate DH

- α-KG DH

- (steps 1, 3, 4)

regulation points of TCA cycle: inhibition and activation

- inhibited by ATP/NADH

- activated by ADP/Ca2+

- allosteric regulation

regulation points of TCA cycle

balances energy demand with fuel supply

amphibolic nature of TCA cycle

- catabolic and anabolic

- central metabolic hub/crossroads that impacts many cellular functions

catabolic nature of TCA cycle

oxidizes acetyl-CoA -> CO2

anabolic nature of TCA cycle

provides precursors for biosynthesis

the Warburg Effect

- cancer cells favor aerobic glycolysis -> formation of lactate, even with oxygen

- reduced reliance on TCA/oxidative phosphorylation in mitochondria

- fuels rapid cell prolifieration

role of NADH and FADH2 in respiration

- NADH and FADH2 = key electron donors

- carry high energy electrons to ETC

- drive proton pumping and ATP synthesis

reduction

gaining electrons

oxidation

loss of electrons

reducing power

ability to donate electrons in redox

reducing power: redox (overview)

- defined by reduction potential (ΔE°')

- difference in potentials can be converted to free energy change (Nernst equation)

- energy released drives proton pumping and ATP synthesis

reduction potential (ΔE°')

negative value is strong electron donor

Nernst equation

ΔG°' = -nFE°'

- difference in potentials converted to free energy change

NADH pathway features

- produced by glycolysis, PDH, TCA cycle

- delivers electrons to Complex I in ETC

- yields ~2.5 ATP per NADH

shuttles for cytosolic NADH

- NADH from glycolysis cannot cross IMM

- malate-aspartate shuttle (efficient)

- glycerol-3-phosphate shuttle (less efficient)

malate-aspartate shuttle does what?

transfers electrons through malate to get across IMM

FADH2 pathway features

- generated in TCA (succinate DH) and β-oxidation

- donates electrons via Complex II

- ~1.5 ATP per FADH2

electron carriers into ETC -> ATP