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PATHWAYS: MITOCHONDRIAL

Fatty acid oxidation Lactate metabolism Oxidative phosphorylation   Composition     Complex I     Complex II     Complex III     Complex IV     Complex V     Combined deficiencies       I, II, III       I, III, IV   Pathways   Measurement methods Mitochondrial disorders

Oxidative Phosphorylation Modified from MW King

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OXIDATIVE PHOSPHORYLATION

Mitochondrial respiratory chain Location: Inner mitochondrial membrane Composition > 80 peptides organized in 5 enzymatic complexes (I-V) Electron shuttle molecules: Coenzyme Q (CoQ); Cytochrome c (Cyt c) Overall actions: Produces ATP from the reduction of oxygen to generate energy for cellular function Pathway Receives electrons generated by donors in intermediary metabolism Electrons sequentially transferred through redox groups to final acceptor, oxygen Free energy generated: Used to pump protons from mitochondrial matrix to intermembrane space Generates electrochemical gradient across inner mitochondrial membrane Protein flux back into mitochondrial matrix through Complex V is coupled to ATP synthesis See: Animated diagram of proton pump & ATP synthesis Other mitochondrial functions Beta oxidation of fatty acids Biosynthesis: Pyrimidines; Amino acids; Phospholipids; Nucleotides; Heme

MITOCHONDRIAL RESPIRATORY CHAIN: COMPOSITION
Complex	I	II	III	IV	V
Enzyme	NADH-CoQ Reductase	Succinate-CoQ Reductase	CoQ-Cytochrome C Reductase	Cytochrome C Oxidase	ATP Synthase
Inhibitor	Rotenone Amytal	TTFA malonate	Antimycin A	Cyanide Carbon Monoxide Azide	Oligomycin
Nuclear DNA Subunits	39	4	10	10	~14
Mitochondrial DNA Subunits	7 ND1-6, ND4L	0	1 Cytochrome b	3 Cytochrome oxidase I , II , III	2 ATPase 6 ATPase 8
Flavoprotein	Flavin mononucleotide	FAD (SDHA)
Iron protein	Iron Sulfur (FeS) protein NDUFS1	FeS protein SDHB	Rieske FeS ; Cytochrome (Heme) b, c1	Cytochrome (Heme) a, a3
Other features		Membrane proteins Cytochrome b560 SDHC SDHD		Copper protein
Disorders	General Alpers Alzheimer's/   Parkinsonism Cardiomyopathy Deficiency   Barth   Lethal Infantile Encephalopathy Infantile CNS Leber's Leigh Longevity MELAS MERRF Myopathy ± CNS PEO Spinal cord	General Kearns-Sayre Leigh's Myopathy   Infantile   ± CNS Paraganglioma Pheochromocytoma	General Cardiomyopathy Fatal infantile GRACILE Leber's Myopathy   ± CNS PEO	General Alper's Ataxia Deafness Leber's Leigh's Myopathy   Infantile     Fatal     Benign   Adult   Rhabdomyolysis PEO, KSS, MNGIE MERRF, MELAS	Cardiomyopathy Encephalopathy Leber's Leigh Multisystem NARP MC5DN5 HUMOP2
Notes Most mitochondrial encephalomyopathies are associated with mutations in mitochondrial DNA Nuclear mutations ® Defects in respiratory chain Leigh's: Flavoprotein subunit of succinate dehydrogenase (complex II) : Fatal multisystemic complex I deficiency: Infantile onset NADH Dehydrogenase (ubiquinone) Fe-S Protein 4 18-kD (AQDQ) subunit of complex I Barth syndrome: Tafazzins Hereditary spastic paraparesis 7: Paraplegin ~ 1,000 mitochondrial peptides not involved in the respiratory chain: Encoded by nuclear DNA Superoxide dismutase 2 (SOD2) Intramitochondrial free radical scavenging enzyme Degrades superoxide produced as a byproduct of oxidative phosphorylation

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COMPLEX I (NADH-Ubiquinone Oxidoreductase): Features & Deficiency ¹

General Features Functions Disorders

• General: Redox-driven proton pump
  • Couples electron transfer: From NADH to ubiquinone
  • Transmembrane proton pumping: Contributes to proton motive force used for ATP synthesis
  • Contributes to formation of mitochondrial reactive oxygen species (ROS)
• Complex I: Features ³
  • Molecular mass: ~1MDa
  • L-Shaped
    • Hydrophobic arm: Embedded in inner mitochondrial membrane
    • Other arm: Protrudes into mitochondrial matrix
  • Composition
    • Largest respiratory chain complex
      • 45 protein subunit assembly
        • 7 Mitochondrial encoded proteins
        • 38 nuclear encoded proteins
        • Catalytic core
          • 14 proteins: Highly conserved
          • Located in protruding arm of complex
          • Fulfills complete function of Complex I
          • Components
            • mtDNA encoded subunits (7)
              • Hydrophobic
              • ND1, ND2, ND3, ND4, ND4L, ND5, ND6
            • Nuclear encoded subunits (7)
              • Hydrophilic
              • NDUFS1, NDUFS2, NDUFS3, NDUFS7, NDUFS8, NDUFV1, NDUFV2
        • Other ("Accessory") subunits (31)
          • Functions: Assembly, Stability & Regulation of Complex I
      • Redox cofactors
        • Flavin mononucleotide (1)
        • Iron-sulphur clusters (8)
          • Form a chain through hydrophilic domain
        • Function: Ensure electron transfer from NADH to ubiquinone
    • Structure
      • L-shaped
      • One arm: Integrated into inner mitochondrial membrane; P-module
      • Second arm: Protrudes into mitochondrial matrix; Q- & N-modules
    • Major subunits
      • Flavoprotein
      • Iron-sulfur protein
      • Hydrophobic fraction
    • Functional modules
      • N-module: NADH dehydrogenase
        • Location: Matrix-protruding arm
        • Responsible for: Oxidation of NADH into NAD⁺
        • Transfer of electrons: Over flavin & iron-sulfur centers to final N2-iron-sulfur center
      • Q-module: Ubiquinone reduction
        • Location: Interface of membrane & matrix-arm
        • Transfers electrons further into ubiquinone reduction site (Includes ND1 subunit)
      • P-module: Proton translocation
        • Membrane embedded
        • Contains remaining mitochondrial DNA encoded subunits
        • Links NADH oxidation to proton translocation from matrix into intermembrane space (IMS): Conformational mechanism
        • Subdivided into 2 domains
          • Proximal (P_P) domain: Contains ND2, ND3, ND6, ND4L
          • Distal domain (P_D): Contains ND4, ND5; Proton transporter pathway
      • Assembled separately
    • Super complexes: Associations with other OXPHOS complexes
      • Complex I + Complex III-dimer (I/III₂)
      • Complex I + Complex III-dimer + Complex IV copies (I/III₂/IV_n)
    • Subunits involved in Complex I structure
      • Core subunits
        • Nuclear DNA encoded
          • NDUFS1: Childhood encephalopathy (MC1DN5); Most common Complex I mutations (3%)
          • NDUFS2: Cardiomyopathy + Encephalomyopathy (MC1DN6)
          • NDUFS3: Leigh (MC1DN8)
          • NDUFS7: Leigh (MC1DN3)
          • NDUFS8: Leigh (MC1DN2)
          • NDUFV1: Childhood encephalopathy (MC1DN4)
          • NDUFV2: Encephalopathy + Cardiomyopathy (MC1DN7)
        • Mitochondrial DNA encoded
          • ND1
          • ND2
          • ND3
          • ND4
          • ND4L
          • ND5
          • ND6
        • General clinical: Null mutations unusual
      • Supernumerary subunits
        • Single transmembrane domain (STMD) subunits
          • General
            • May assist mitochondrially encoded, hydrophobic subunits to organize their transmembrane helixes
          • NDUFA1 (MWFE)
            • Primarily expressed in heart & skeletal muscle
            • Disorders: Encephalopathies (MC1DN12)
          • NDUFA3
          • NDUFB1
          • NDUFB2
          • NDUFB3: Severe lethal mitochondrial complex I deficiency (MC1DN25)
          • NDUFB4
          • NDUFB11: Microcephaly + Linear Skin Defects (MLS) (MC1DN30)
          • NDUFB5
          • NDUFB6
          • NDUFC1
          • NDUFC2 : Encephalopathy
        • NDUFA2: Encephalopathy & Cardiomyopathy (MC1DN13)
        • NDUFA6: Encephalopathy (MC1DN33)
        • NDUFA8: Encephalopathy (MC1DN37)
        • NDUFA9: Leigh syndrome; Dystonia (MC1DN26)
        • NDUFA10: Leigh syndrome (MC1DN22)
        • NDUFA11: Encephalopathy & Cardiomyopathy (MC1DN14)
        • NDUFA12: Leigh syndrome (MC1DN23)
        • NDUFA13: Encephalopathy & Optic atrophy (MC1DN28)
        • NDUFAB1 (SDAP) : Carrier of fatty acid chain
        • NDUFB7
        • NDUFB8: Leigh-like (MC1DN32)
        • NDUFB9: Hypotonia (MC1DN24)
        • NDUFB10: Lethal Multisystem Mitochondrial Disorder (MC1DN35)
        • NDUFS6: Lethal Infantile Mitochondrial Disease (MC1DN9)
    • Subunits involved in regulation of Complex I activity
      • NDUFS4 (AQDQ)
        • Functions: Increased Complex I activity with phosphorylation
        • Disorders
          • Multisystem childhood encephalopathy with Complex I deficiency (MC1DN1)
          • Leigh syndrome
    • Proteins involved in Complex I assembly
      • Disease, General: Null mutations common
      • NDUFAF1: Cardiomyopathy + Encephalomyopathy (MC1DN11)
      • NDUFAF2 (NDUFA12L): Childhood encephalopathy (MC1DN10)
      • NDUFAF3: Fatal Neonatal (MC1DN18)
      • NDUFAF4: Encephalopathy (MC1DN15)
      • NDUFAF5: Lethal neonatal (MC1DN16)
      • NDUFAF6: Leigh syndrome (MC1DN17)
      • NDUFAF8: Leigh-like (MC1DN34)
      • NUBPL: Encephalomyopathy (MC1DN21)
      • ACAD9: Fatigue & Exercise intolerance; Most missense mutations (MC1DN20)
      • TMEM126B: Fatigue & Exercise intolerance (MC1DN29)
      • FOXRED1: Leigh syndrome (MC1DN19)
      • Ecsit
      • AIF (AIFM1; PDCD8)
      • Ind1
      • TIMMDC1 (C3orf1) : Encephalopathy (MC1DN31)
    • Other
      • DNAJC30: LHON
      • ELAC2: Cardiomyopathy, Hypertrophic (COXPD17)
      • NDUFA13 : Thyroid carcinoma (Hurthle cell)
      • MTHFR deficiency
      • MGME1: PEO + Myopathy (MTDPS11)
      • MTFMT: Leigh-like (MC1DN27)
      • NAXE: Ataxia, Myelopathy & Skin disease (PEBL)
      • SFXN4: Anemia + Mitochondriopathy (COXPD18)
      • VARS2: Microcephaly & Epilepsy (COXPD20)
  • General structure
    • L-shaped
    • Hydrophobic arm
      • Contains mtDNA-encoded subunits
      • Attaches complex to inner mitochondrial membrane: Embedded in membrane
      • ? Formed by 2 small & large subcomplexes (in Neurospora)
        • Role in assembly played by: CIA30; CIA84
    • Hydrophilic peripheral arm
      • Flavoprotein
      • Contains NADH binding site & redox active centers
      • Extends into mitochondrial matrix
    • Iron–Sulphur protein fraction
      • Facilitates further electron transport to hydrophobic fraction
  • Location: Parts in
  • Mitochondrial inner membrane
  • Mitochondrial matrix
  • Complex I: Associations (Respirasome)
    • Supercomplex of I, III, IV
    • Stabilizes structure of Complex I
    • Stoichiometry of I:IIII:IV = 1:2:4
    • Deficiency in other Complexes may produce loss of Complex I function
• Complex I: Functions
  • Transport of electrons from NADH to ubiquinone
  • Electron source: NADH
  • Co-factor: Flavin mononucleotide
  • Transport: via eight redox groups, iron–sulphur clusters
  • Electron acceptor: Ubiquinone
  • Ubiquinone function: Transfers of electrons to next complex in the chain (Complex III)
  • Simultaneous shunting of protons
    • Out of mitochondrial matrix
    • Across inner mitochondrial membrane
    • Into intermembrane space
  • Stoichiometry: 4H⁺/2e^-
• Disorders
  • Complex 1 disorders: General
    • Lactate levels & muscle morphology may be normal
    • Most common clinical phenotype in childhood: Leigh syndrome
    • Most common cause of Complex I deficiency: Nuclear gene mutations
    • Increased age: Associated with reduced Complex I activity ⁶
    • Inheritance: Usually recessive
      • Exception: NDUFA1 - X-linked Encephalopathies
  • Complex I-related molecules
  • Complex I ± Other complexes deficient
    • Alper's
    • Alzheimer's/Parkinsonism
    • Cardiomyopathy
    • Deficiency: Barth; Infantile CNS
    • Encephalopathy, Adult onset
    • Leber's (LHON)
    • Leigh
    • Longevity
    • MELAS
    • MERRF
    • Myopathy
    • ± CNS
    • PEO
    • Spinal cord
    • Benign infantile mitochondrial myopathy with reversible cytochrome c oxidase (COX) deficiency
    • Sertraline treatment
  • Isolated Complex I deficit: mtDNA mutations
    • MELAS: tRNA^Leu (A3243G & T3271C)
    • Myopathy: tRNA^Leu (T3250C, A3251G & A3303G)
    • Riboflavin Sensitive myopathy: tRNA^Leu
    • Leber's (LHON): tRNA^Lys (G11778A), ND1 (G3460A) & ND6 (T14484A)
    • MERRF: tRNA^Lys (G8363A), ND1 (A8344G), tRNA^{Ser (MTTS2)}
    • Leigh syndrome: ND4 (G14459A)
    • Long QT syndrome: tRNA^leu (T3394C)
    • Diabetes & Fanconi syndrome: Multiple deletion
    • Ataxia, Hypogonadism & Choroidal dystrophy: Multiple deletion
  • Isolated Complex I deficit: Nuclear mutations (MC1DN)
    • Clinical features: General
      • Nuclear mutations more common than mitochondrial
      • Onset: Childhood; Mean = 4 to 5 months
      • Male:Female = 3.5:1
      • Prognosis: Death in 1st 2 years in 67%; ? Better with normal blood lactate
      • Lactic acidosis: Blood 85%; CSF 90%
      • Inheritance: Usually autosomal recessive
      • MRI: Abnormal
    • Specific syndromes
      • Fatigue & Exercise intolerance: ACAD9
      • Leigh syndrome: NDUFS3; NDUFS4; NDUFS7; NDUFS8; NDUFAF6
      • Optic neuropathy
      • Encephalopathy & Cardiomyopathy: NDUFA2, NDUFA11
      • Macrocephaly with progressive leukodystrophy: NDUFV1
      • Encephalomyopathy: NDUFV1; C6ORF66; NUBPL
      • Epileptic encephalopathy: SLC25A10
      • Hepatomegaly with renal tubulopathy
      • Lethal neonatal: NDUFAF3; NDUFS6; NDUFAF5
      • Cardiomyopathy + Encephalomyopathy: NDUFS2; NDUFV2; NDUFAF1
      • Childhood encephalopathy: NDUFS1; MYC-induced mitochondrial protein; NDUFA1; NDUFAF2; NDUFAF4; ISCA2
      • Trichloroethylene toxicity
      • Severe neonatal lactic acidosis with mtDNA depletion: SUCLG1; Multiple complex deficiencies
      • Neonatal cardiomyopathy + Lactic acidosis
      • Portneuf spastic ataxia with leukoencephalopathy (SPAX3): MARS2
      • Microcephaly & Epilepsy: VARS2
    • Other
      • Age: Increased frequency of isolated complex I deficiency with Age > 50 years ⁶

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COMPLEX II (Succinate Dehydrogenase-CoQ Oxoreductase): Features & Deficiency

• Functions
  • Mitochondrial respiratory chain
    • Catalyzes oxidation of succinate to fumarate
    • Transfers electrons to ubiquinone pool of respiratory chain
  • Krebs cycle
• Composition
  • Subunits: General
    • Number: 4
    • All nuclear encoded
    • Subunits A & B: Form succinate dehydrogenase (SDH) enzyme activity
    • Subunits C & D: anchor enzyme to inner mitochondrial membrane
  • Flavoprotein: FAD (SDHA; Fp)
    • Functions: Catalytic site; Covalently bound FAD cofactor
    • Mutations
      • Leigh syndrome with Complex II deficiency
      • Late onset neurodegenerative disorder
  • Iron-Sulfur protein: SDHB (Ip)
    • Function: Electron transfer between FAD and membrane-bound quinone
    • Structure: Contains three different iron-sulphur clusters
    • SDHB mutations
      • Reduced tumor suppression
      • Neoplasms: Pheochromocytoma & Paraganglioma
  • Cytochrome b subunits: SDHC ; SDHD
    • Integral membrane proteins: Bind Fp & Ip to matrix
    • SDHC & SDHD mutations: Paraganglioma
• Location of Complex II
  • Matrix side of mitochondrial inner membrane
  • Binding to membrane is dependent on 2 small (15.5 and 13.5 kDa) proteins SDHC & SDHD
• Complex II inhibitor: 3-nitropropionic acid
• Disorders (MC2DN)
  • Selective biochemical defect of Complex II
    • SDHA mutations
      • Leigh syndrome
      • CMD 1GG: Cardiomyopathy, Familial dilated
    • SDHAF1 mutations: Infantile leukoencephalopathy
  • Complex I, II & III deficiency
    • Fe-S disorders
    • Muscle fiber atrophy: Complex II & II+III > I
  • Neoplasms: Paragangliomas & Pheochromocytomas
    • SDHAF2, SDHB, SDHC, SDHD mutations

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COMPLEX III (CYTOCHROME REDUCTASE): Features & Deficiency

Complex III Features

• Composition
  • Nuclear subunits
    • Number: 10
    • Components
      • Respiratory
        • Cytochrome c1 (CYC1)
        • Rieske FeS protein (UQCRFS1)
      • Core proteins
        • Ubiquinol-cytochrome c reductase core protein I (UQCRC1; QCR; Subunit 1)
          • May mediate formation of complex between cytochromes c and c1
        • Ubiquinol-cytochrome c reductase core protein II (UQCRC2; QCR2; Subunit 2)
          • Required for assembly of complex III
      • Low molecular weight proteins
        • UQCRH (Subunit 6)
          • May mediate formation of complex between cytochromes c and c1
        • Ubiquinone-binding protein (UQBC; UQPC; UQCRB; UQBP; Subunit 7)
          • Redox-linked proton pumping
        • UQCRQ (Subunit 8)
          • Binds to ubiquinone
        • Ubiquinol-cytochrome C reductase complex, 7.2-KD Subunit (UCRC; UQCR10; Subunit 9)
          • Interacts with cytochrome c1
        • UQCR (UQCR11; Subunit 10)
          • May function as iron-sulfur protein binding factor
        • Cleavage product of UQCRFS1 (Cytochrome b-c1 complex subunit 11)
  • Mitochondrial subunits
    • Number: 1
    • Component: Cytochrome b (MT-CYB) (Respiratory subunit): Binds to ubiquinone
• Location of Complex III: Inner mitochondrial membrane
• Associations
  • Supercomplex of Complexes I, III, IV
  • Association of Complexes III & IV may be stabilized by cardiolipin
  • Defects in cardiolipin remodeling: Barth
• Complex III synthesis related protein: BCS1L

Complex III Functions

• Transfers electrons from ubiquinol to cytochrome c
• Coupled with transfer of electrons across inner mitochondrial membrane
• Contains 3 redox centers
• Cytochrome b
• Cytochrome c
• Rieske FeS protein (UQCRFS1)

Complex III disorders

• Selective complex III biochemical defect (MC3DN)
  • Subunits
    • Cytochrome b (MTCYB) : Mitochondrial; Sporadic
      • Leber's
      • Myopathy ± CNS
    • CYC1: Encephalopathy & Hyperglycemia (MC3DN6)
    • UQCRB (MC3DN3)
    • UQCRC1
    • UQCRC2 (MC3DN5)
    • UQCRFS1 (MC3DN10)
    • UQCRH (MC3DN11)
    • UQCRQ (MC3DN4)
  • Assembly factors
    • BCS1L (GRACILE, MC3DN1)
    • LYRM7 (MC3DN8)
    • UQCC2 (MC3DN7)
    • UQCC3 (MC3DN9)
    • TTC19 (MC3DN2)
• Other defects
  • Cardiomyopathy
  • Fatal infantile
  • PEO
    
  • Tubulopathy, Encephalopathy & Liver failure
  • Chromosome 15q11-13 duplication ⁵: Developmental delay with high CK or NH₃

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COMPLEX IV (CYTOCHROME OXIDASE): Features & Deficiency

Complex IV Composition & Related Proteins

• Nuclear subunits
  • Number: 10
  • Presumed to play a structural & regulatory role in COX
• Mitochondrial subunits: 3
  • Subunits
    • Catalytic
      • MT-CO1
      • MT-CO2
    • Core structural
      • MT-CO3
  • Properties: Largest & most hydrophobic COX subunits
  • Form catalytic core of COX
  • Contains 3 copper atoms & 2 heme A molecules
    • Serve as prosthetic groups in holoenzyme
    • Directly involved in electron transfer
• Assembly factors related to COX
  • Essential components of COX biosynthetic pathway
  • Expression of individual COX subunits
  • Provide prosthetic groups to the apoenzyme
  • Factors include: SURF-1; SCO1; SCO2; COX 10; COX 17

Nuclear mutations (MC4DN)

• Mutations in proteins required for assembly of holocomplex
  • Surfeit-1 (SURF-1) : Leigh syndrome (French-Canadian type) (MC4DN1)
    ● Chromosome 9q34; Recessive
    • COX subunits reduced: All except Va & Vb
  • SCO1 : Neonatal hepatic failure & Ketoacidotic coma ²
    ● Chromosome 17p13.1; Recessive
  • SCO2 : Cardioencephalomyopathy, fatal infantile (MC4DN2)
    ● Chromosome 22q13; Recessive
    • COX subunits reduced: I & II
  • COX5A: Systemic (MC4DN20)
  • COX10 (Heme A:farnesyltransferase) : Ataxia; Encephalopathy
    ● Chromosome 17p13.1-q11.1; Recessive
    • COX subunits reduced: II
  • COX11: Encephalopathy (MC4DN23)
  • COX14 (c12orf62) : Encephalocardiomyopathy, Fatal neonatal lactic acidosis
    ● Chromosome 12q13.12; Recessive
    • COX subunits reduced: I, II, IV
  • COX15 : Hypertrophic cardiomyopathy or Leigh syndrome
    ● Chromosome 10q24; Recessive
  • COX16: Encephalopathy + Cardiomyopathy
  • COX18: Encephaloneuropathy
  • COX20 (FAM36A): Ataxia + Pyramidal signs
    ● Chromosome 1q44; Recessive
    • Reduced incorporation of COX2 subunit
  • COXFA4: Encephalopathy
  • TACO1 : Leigh syndrome, childhood onset
    ● Chromosome 17q23; Recessive
  • COA3 : Neuropathy + Exercise intolerance
    ● Chromosome 17q21.31; Recessive
  • COA7: SCAN3
    ● Chromosome 1p32.3; Recessive
  • C2orf64 (COA5) : Hypertrophic cardiomyopathy
    ● Chromosome 2q11; Recessive
  • CEP89 (CCDC123) : Developmental delay & Multisystem disorder
    ● Chromosome 19q13.11; Recessive
  • PET100: Leigh
  • PET117: Encephalopathy
• Mutation in mRNA binding protein
  • LRPPRC : Leigh syndrome; Metabolic acidosis
    ● Chromosome 2q16; Recessive
• Mutations in nuclear encoded structural proteins of COX
  • COX6A1: CMT 2
  • COX6A2: Myopathy
  • COX6B1 : Leukodystrophy
    ● Chromosome 19q13.1; Recessive
  • COX7B: Linear Skin Defects
  • COX8A: Leigh + Epilepsy
  • NDUFA4: Leigh
• Leigh syndrome
  • NDUFA4; Chromosome 7p21
  • PET100; Chromosome 19p13
  • COX8A: Leigh + Epilepsy >MRPS34: Leigh
  • FASTKD5; Chromosome 20p13
• Other clinical syndromes
  • Leukodystrophy, Cavitating: APOPT1; Chromosome 14q32
  • Encephalomyopathy
    • FASTKD2; Chromosome 2q33
    • AIFM1; Xq25
    • MRPS25: 3p25
    • TEFM: 7q11
  • COX4I1: Encephalopathy
  • Encephalopathy: TOMM70; 3q12
  • Myopathy with Cataracts: GFER; Chromosome 16p13
  • COX4I2: Pancreas + Anemia

Mitochondrial mutations

• COX I subunit
  • Leber optic atrophy
  • Sideroblastic anemia, acquired idiopathic
  • Encephalopathy with hearing loss
  • Colorectal cancer
  • Exercise intolerance & Myoglobinuria
• COX II subunit
  • Ataxia
  • Myopathy ± CNS
• COX III subunit
  • Leber optic atrophy
  • Myoglobinuria
  • Exercise intolerance
  • Encephalopathy
  • Spastic paraparesis, Mental retardation & Ophthalmoplegia

Other syndromes associated with Complex IV deficiency

• Alexander disease
• Alpers
  • Alpers-Huttenlocher (MTDPS4A): POLG
  • COXPD14: FARS2
• Ataxia
• Cardiomyopathy: MRPL44
• Copper deficiency
• Deafness
• Hyperhomocysteinemia
• Leber's
• Leigh's
• Leukoencephalopathy with ovarian failure: AARS2
• Myopathy
  • Infantile-onset
    • Fatal
    • Benign
  • Adult-onset
    
    • Rhabdomyolysis
    • PEO
    • KSS
    • MNGIE
    • MERRF
    • MELAS

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COMPLEX V (ATP Synthase): Features & Deficiency

• Composition
  • General: 16 subunits
    • mtDNA encoded: 2 subunits
      • Subunit a of F₀: ATP synthase 6
      • Subunit A6L of F₀: ATP synthase 8
    • Nuclear DNA encoded: 14 subunits
  • Integral membrane component: F₀
    • Composed of at 10 subunits
    • mtDNA encodes 2 subunits: ATP synthase 6 (a) & ATP synthase 8 (A6L)
    • Nuclear encoded subunits: b; c₁₂; d; e; f; g; OSCP; F₆
    • Location: Inner mitochondrial membrane
    • Allows protons to pass from mitochondrial intermembrane space to matrix
  • Peripheral moiety: F₁
    • Globular
    • Catalytic
    • Composed of six subunits: α₃; β₃; γ, δ; ε; IF1
    • Nuclear DNA encodes all subunits
    • Uses proton gradient to convert ADP to ATP
    • Assembly factors
      • Human specific: ATP11 (ATPAF1 gene); ATP12 (ATPAF2 gene)
    • Soluble
    • Location: Mitochondrial matrix
    • Catalytic activity
• Function: Couples proton gradient generated by respiratory chain to ATP synthesis
  • Proton flow from intermembrane space to matrix
  • Conversion of ADP + inorganic phosphate to ATP
  • Molecular motor: Proton translocation at interface of subunits c and a
    • Drives rotation of subunit c oligomer
    • Induces conformational changes in F1
    • Facilitates synthesis of ATP
  • Disorders: Content of ATP synthase complex is <30% of controls
• Common features
  • Onset: Neonatal
  • Hpotonia
  • Cardiomyopathy: Hypertrophic
  • Lactic acidosis
  • Hyperammonemia
  • 3-methylglutaconic aciduria
• Mutations (MC5DN)
  • mtDNA mutations
    • General
      • Heteroplasmic
      • More common cause: ATPase 6 mutations
      • Mutation effects
        • Impairs energetic function of F_o proton channel
        • Prevents ATP synthesis
        • Normal rate of ATP hydrolysis
        • Normal concentration of enzyme complex
    • ATP Synthase 6 (mtATP6) disorders ⁷
      • General
        • Inheritance: Maternal
        • Disease onset: 0 to 71 years; Median = 4 years
      • Leigh (MILS)
        • Genetics: High levels (> 90%) of T8993G or T8993C mutations in brain & blood
        • Most common mtATP6 syndrome (38%)
        • Onset age: Median 1.5 years
      • Ataxia: Most common clinical feature (80%)
        • NARP: Intermediate levels (70% to 90%) of T8993G or T8993C mutations in brain & blood
        • Neuropathy, Adult onset
        • Cognitive delay: T9035 ¹⁰¹
        • Mental retardation
        • Leigh, Juvenile
        • SCA with upper motor neuron signs
      • Spastic paraplegia
      • CNS, Other
        • Striatal necrosis,Bilateral : T9176C mutation
        • Seizures + Ocular disorders
        • Learning disability
      • PNS
        • Weakness: Neurogenic; Distal or Proximal
        • CMT-Axonal
        • dHMN
        • Periodic paralysis + Motor neuropathy
        • CNS + Motor
      • MLASA3
      • Cardiomyopathy, Infantile, Hypertrophic
    • ATP Synthase 8 (mtATP8) disorders
      • Cardiomyopathy + Neuropathy
      • Periodic paralysis & Motor neuropathy
  • Complex V: Nuclear encoded protein disorders
    • General effects
      • Often cause loss of entire protein complex
      • Defect
        • At early stage of ATP synthase enzyme assembly
        • Disordered formation of F₁ catalytic part of ATP synthase
      • ATP synthase concentrations: Reduced to ≤ 30%
      • Synthetic & Hydrolytic activities: Severe loss
    • ALDP: AML; ? Complex V activity impaired by VLCFA 26:0 accumulation
    • Mitochondrial complex V (ATP Synthase) Deficiencies, Nuclear type (MC5DN)
      • 1: ATPAF2 (ATP12) (Assembly gene); Congenital multisystem disorder
      • 2: TMEM70 (Biogenesis): Neonatal encephalocardiomyopathy
      • 3: ATP5E (Complex V subunit): Retardation & Polyneuropathy
      • 4A & 4B: ATP5F1A (Complex V subunit); Encephalopathy
      • 5: ATP5F1D; Childhood encephalopathy
      • 6: USMG5 (ATP5MD); Childhood encephalopathy (Leigh-like)
      • 7: ATP5PO, Encephalopathy
    • Cardiomyopathy
    • ATP5A1: Encephalopathy, neonatal (COXPD22)
    • ATP5F1B: HUMOP2

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Combined Complex Deficiencies

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Complexes I, III, IV ± V Deficient

• Causes: Mutations
  • General: Defect in synthesis of mtDNA-encoded proteins
  • Mutations
    • mtDNA
    • Components of mitochondrial translation apparatus encoded by nuclear genes
• Synthesis of 13 mitochondrial gene-encoded proteins
  • Occurs on a dedicated mitochondrial translation apparatus
  • Requires tRNAs and ribosomal RNAs (rRNAs) encoded in mtDNA
  • Other factors
    • Translation factors
    • Mitochondrial ribosomal (mitoribosome) proteins: All encoded by nuclear genes
    • Mammalian initiation factors: IF2 & IF3
    • Elongation factors: EFTu, EFTs, EFG1 & EFG2
    • Release factor: RF1
    • Ribosomal recycling factor: RRF
  • Mitoribosomes
• Disorders
  • mtDNA: Depletion syndromes
  • Nuclear gene mutations: Other (COXPD)
    • AARS2: Cardiomyopathy, Infantile (COXPD8)
    • AGK: Sengers
    • AIFM1: Encephalopathy (COXPD6)
    • ANT1: Cardiomyopathy
    • APOO: Encephalopathy
    • ATP5A1: Encephalopathy, neonatal (COXPD22)
    • c12orf65: Leigh-like syndrome + Optic atrophy & Ophthalmoplegia (COXPD7)
    • C1QBP: Cardiomyopathy +
    • CARS2: Epileptic encephalopathy + Movements (COXPD27)
    • COQ7: Encephaloneuropathy + Systemic features
    • CRLS1: Encephalopathy +
    • EARS2: Leukoencephalopathy (COXPD12)
    • EFG1: Hepatoencephalopathy (COXPD1)
    • EFTs (TSFM) (COXPD3)
      • Fatal mitochondrial encephalomyopathy
      • Fatal hypertrophic cardiomyopathy
    • EFTu: Encephalopathy (COXPD4)
    • ELAC2: Hypertrophic cardiomyopathy (COXPD17)
    • ENDOG: PEO + Myopathy
    • FARS2: Alpers hepatoencephalopathy (COXPD14)
    • FBXL4: Encephalopathy
    • GATB: Multisystem disorder, infantile
    • GATC: Multisystem disorder, infantile
    • GTPBP3: Encephalopathy & Hypertrophic cardiopmyopathy (COXPD23)
    • LYRM4: Respiratory distress & Hypotonia (COXPD19)
    • MARS2: Congenital CNS (COXPD25)
    • MIEF2: Myopathy & Fatigue (COXPD49)
    • MIPEP: Encephalopathy & cardiomyopathy (COXPD31)
    • Mitoribosomal subunits
    • MLASA: Myopathy, Lactic acidosis & Sideroblastic anemia
    • MRPS25: Encephalopathy (COXPD50)
    • MTFMT: Leigh (COXPD15)
    • MTO1: Cardiomyopathy (COXPD10)
    • NARS2: Encephalopathy or Myopathy (COXPD24)
    • NSUN3: Encephalomyopathy (COXPD48)
    • PNPT1: Encephalomyopathy (COXPD13)
    • QRSL1: Multisystem disorder
    • RARS2: PCH6
    • RMND1: Encephaloneuropathy (COXPD11)
    • SFXN4: Macrocytic Anemia & Mitochondriopathy (COXPD18)
    • SLC25A4: Encephalomyopathy
    • SLC25A26: Encephalomyopathy (COXPD28)
    • SUCLG1: Severe neonatal lactic acidosis
    • TARS2: Axial hypotonia & Psychomotor delay (COXPD21)
    • TIMM29: Sengers
    • TRIT1: Encephalopathy
    • TRMT5: Exercise intolerance; Cardiomyopathy (COXPD26)
    • TRMT10C: Encephalopathy, Infantile
    • TRMU: Acute Infantile Liver Failure (COXPD30)
    • TRNT1: Encephalopathy
    • TXN2: Neurodegeneration (COXPD29)
    • VARS2: Microcephaly & Epilepsy (COXPD20)
    • YARS: Myopathy + Lactic acidosis & Anemia
  • Acquired
    • Muscle ischemia, chronic: Peripheral arterial disease

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Complexes I, II & III Deficient

• Causes: Nuclear mutations in proteins involved in Iron-sulfur-cluster assembly
• Fe-S cluster disorders
  • Muscle biochemistry: Complex II ± I or III deficiency
  • Fe-S cluster containing or synthetic proteins
  • Muscle fiber atrophy
  • Sarcopenia
  • Liver disease, Severe

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Lactate metabolism ⁴

• Production
  • Pathways
    • Glycogenolysis
    • Glycolysis
  • Increased production with
    • Greater exercise power output
    • Increased oxygen uptake
  • Produced even under fully aerobic conditions
• Shuttles
  • Molecules: Lactate exchange facilitators
    • Membrane transporters: Monocarboxylate transport proteins (MCTs)
      • Stereo-selective for L-(+)-lactate
      • pH dependent
      • Sarcolemmal lactate transporters may have role in regulation of intracellular pH
      • Lactate transport in skeletal muscle: MCT1 (SLC16A1) & MCT4 (SLC16A3)
        • Inactivity: Reduces MCT1 & MCT4 expression
        • Training: Increases MCT1 & MCT4 expression
        • Brief, high intensity exercise: Reduces MCT1 & MCT4 expression
    • Scaffolding proteins
  • Cell-cell lactate exchanges between
    • White-glycolytic & red-oxidative fibres in a working muscle bed
    • Working skeletal muscle & heart
    • Tissues of net lactate release & gluconeogenesis
    • Astrocytes & neurons in brain: Linked to glutamatergic signalling
  • Intracellular lactate exchanges
    • Mitochondrial lactate oxidation complex
      • Proteins involved
        • Mitochondrial lactate/pyruvate transporters (MCT)
        • Scaffolding glycoprotein basigin (CD147) : Chaperone protein
        • Lactate dehydrogenase
        • Cytochrome oxidase
      • Location: Mitochondrial reticulum
      • Function
        • Proteins work in conjunction to permit lactate oxidation in actively respiring cells
        • Establishes concetration & proton gradients
        • Needed by cells with high mitochondrial densities: Cardiac & Skeletal muscle
    • Sarcolemma
      • Protein: Sarcolemmal lactate/pyruvate transporter MCT1 (SLC16A1)
    • Training effects: Change expression of related proteins
• Disposal
  • Pathways
    • Oxidative metabolism
      • Rest: 50%
      • Exercise: 75%
    • Cori cycle
      • Contribution: 25% during exercise
      • Pathway: Conversion of lactate to glucose (gluconeogenesis)
  • Increased disposal with
    • Endurance training: Reduces arterial lactate
• Disorders
  • SLC16A1 Lactate transporter defect
    • Epidemiology: 2 patients
    • Genetics: Heterozygous missense mutations; Lys204Glu, Gly472Arg
    • SLC16A1 protein
      • Transporter defect location: Erythrocytes & Muscle
    • Clinical: Pain after exercise
    • Lab: Erythrocyte lactate clearance rates decreased to 40% to 50% of normal control
  • Lactate dehydrogenase, M (muscle) subunit
  • Basigin (BSG) : Blood group OK

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Krebs (TCA) Cycle

Disorders

By Narayanese, WikiUserPedia, YassineMrabet, TotoBaggins

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Return to Neuromuscular Home Page
Return to Mitochondrial disorders

References
1. Human Mutation 2000;15:123-134, IUBMB Life 2011; Online July, Biochimica et Biophysica Acta 2016; 1857:902–914, Curr Opin Struct Biol 2020 Aug;63:1-9
2. Am J Hum Genet 2000;67
3. Curr Opin Neurol 2004;17:179–186
4. Sports Med 2007;37:341-343
5. J Child Neurol 2009 Jun 17
6. Muscle Nerve 2017;56:122-128
7. Ann Neurol 2019 Jun 11

11/16/2025