Mitochondrial dysfunction

Mitochondrial dysfunction and mitochondrial diseases

OVERVIEW

Mitochondria are the intracellular organelles that produce the bulk of the body’s energy currency (ATP)

• they are derived from endosymbiotic prokaryotes around the time of the origin of eukaryotic cells
• eukaryotic cells are entirely dependent on mitochondria for energy production

Mitochondrial dysfunction plays a role in specific mitochondrial diseases and may be important in critical illness

• Mitochondrial diseases can present in children or in adulthood, usually as neuromuscular disorders
• Mitochondrial dysfunction may contribute to multi-organ dysfunction syndrome (MODS) in critical illness, such as that occuring in severe sepsis syndromes
• Most data regarding mitochondrial dysfunction in organs susceptible to failure in critical care diseases (liver, kidney, heart, lung, intestine, brain) is from animal models
• There is no clear therapeutic strategy how acquired mitochondrial dysfunction can be improved

MITOCHONDRIAL STRUCTURE AND COMPONENTS

Mitochondria have two lipid membranes that demarcate the mitochondria from the cytosol

• inner membrane
  • houses the mitochondrial respiratory chain
  • forms an ionic barrier allowing the creation of a transmembrane proton gradient
  • contains the mitochondrial matrix, which contains the enzymes involved in the citric acid cycle and β-oxidation necessary for carbohydrate and fat metabolism
• outer membrane
  • a porous membrane allowing passive diffusion of low molecular weight substances between the cytosol and the intermembrane space

Mitochondria generates energy in the form of ATP as electrons pass along the mitochondrial respiratory chain

• as electrons pass through complexes I–IV in succession protons are simultaneously extruded generating an electrochemical gradient across the inner mitochondrial membrane
• Complex V is ATP synthase, which uses the proton gradient to drivethe formation of ATP from ADP and phosphate

Mitochondrial DNA (mtDNA)

• inherited via the maternal lineage
• genome consists of multiple copies of closed circular loops of dsDNA (e.g. >100 000 copies in oocytes)
• encodes the 13-polypeptides essential for oxidative phosphorylation, as well as two ribosomal RNA genes and 22 tRNA genes required for their production
• higher mutation rate than nuclear DNA due to the hostile environment of the mitochondrial matrix; though ‘heteroplasmy’ partially protects against the deleterious effects of mutations (heteroplasmy is the presence of multiple copies of wildtype and mutant mtDNA)
• mitochondria undergo frequent fission and fusion events allowing exchange of genetic material between mitochondria

Mitochondria are dependent on the import of cytosolic proteins for maintenance of mitochondrial function

• only about 15% of mitochondial proteins are derived from the endosymbiont lineage
• the rest are derived from nuclear DNA

ROLE OF THE MITOCHONDRIA

Proper mitochondrial function is critical for normal performance and survival of cells; functions include:

• production of energy (ATP)
• activation of apoptosis when ATP levels are low
• production of reactive oxygen species (ROS)
• cell signaling
• intracellular calcium regulation
• synthesis of important biomolecules
  • site of production (e.g., cortisol) or action (e.g., triiodothyronine, estrogen) of many hormones
  • biosynthesis of heme and iron-sulfur clusters
• heat generation and thermoregulation

Mitochondrial dysfunction can lead to pathological conditions resulting in various human diseases ROLE IN MULTIPLE ORGAN DYSFUNCTION SYNDROME (MODS)

Measures of mitochondrial dysfunction in MODS correlate with:

• worse outcomes
• more severe organ dysfunction

It is unclear whether these associations are causative or simply epiphenomena, but a role of mitochondrial dysfunction in MODS is supported by the following:

• MODS can occur in the absence of macrovascular defects of evidence or impaired oxygen delivered (normal tissue oxygen tensions)
• evidence of decreased oxygen consumption in sepsis
• organs tend to be histologically intact in MODS with minimal cell death
• recovery of organ function over days-to-weeks  is often seen in MODS survivors, even in organs that are poorly regenerative
• markers of mitochondrial biogenesis typically precede clinical improvement and improved organ dysfunction
• systemic inflammation has multiple effects on mitochondria (see below)

EFFECTS OF SYSTEMIC INFLAMMATION ON MITOCHONDRIA

The inflammatory cascade can culminate in mitochondrial dysfunction due to:

• impaired oxygen delivery leads to decreased ATP production, which can trigger apoptosis
• ROS can directly inhibit mitochondrial function and damage mitchondrial proteins and lipids
• hormonal effects, such as the sick “euthyroid” state
• downregulation of gene expression of mitochondrial proteins

Responses at the cellular level include:

• short-term increase on non-mitochondrial ATP production
• decreased metabolic rate, allowing adaptation to low ATP levels
• apoptosis if ATP levels fall below threshold levels
• mitophagy and mitochondrial regeneration

The response at the organ level manifests as multi-organ dysfunction syndrome (MODS), reflecting bioenergetic shutdown

THERAPIES FOR ACQUIRED MITOCHONDRIAL DYSFUNCTION

No therapies are proven or used in current mainstream clinical practice

Putative therapies include:

• Antioxidants
• induction of a hypometabolic state through therapeutic hypothermia, carbon monoxide or hydrogen sulfide
• stimulating mitochondrial biogenesis

GENETIC MITOCHONDRIAL DISEASES

Overview

• mitochondrial diseases may be due to nDNA or mtDNA mutations and may present in children or adults
• may have non-specific symptoms or present ‘classically’, usually with neuromuscular deficits, and may develop multi-system manifestations
• earlier onset implies more severe disease

Cause

• a single genotype may have high phenotypic variation, and different genotypes may manifest with the same phenotype
• unidentified nuclear DNA (nDNA) mutations account for most paediatric presentations
  • usually autosomal recessive
  • about 25% of paediatric mitcondrial disease is due to mtDNA mutations
• mtDNA mutations are more likely to manifest at later ages
  • most mitochondrial diseases occur when the number of copies of mutant mtDNA exceeds a threshold, negating the benefit of heteroplasmy (the coexistence of multiple copies of wildtype and mutant mtDNA)
  • Leber’s hereditary optic neuropathy (LHON) is an exception, selection pressures favour the multiplication of the mutant mtDNA to such an extant that homoplasmy results (mitochondria only contain mutant mtDNA, not wildtype mtDNA)
• Mitochondrial disease commonly presents with a combination of muscle and brain involvement
  • mutant mtDNA tends to accumulate in post-mitotic tissues and is more likely to manifest in tissues with high metabolic requirements
  • other non-random mechanisms may contribute to differential segregation in different tissues as cells divide

Examples

• Mitochondrial disease with onset in infancy or early childhood
  • Leigh syndrome
  • Depletion syndromes
  • Pearson syndrome
  • Kearns-Sayre syndrome
• Mitochondrial disease with onset in late childhood or adult life
  • Mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS)
  • Maternally inherited diabetes and deafness
  • Neuropathy, ataxia and retinitis pigmentosa (NARP)
  • Mitochondrial neuro-gastrointestinal encephalopathy
  • Chronic progressive external ophthalmoplegia

History

• age of onset of symptoms
  • different disorders may present in childhood or in adulthood
•  inheritance
  • review maternal health and obstetric history
  • family history of neonatal or childhood deaths
• typically have neurological and muscular manifestations
  • e.g. seizures, migraine, stroke-like episodes, neuropathy and dystonia
  • e.g. mitochondrial myopathy (weakness), cardiomyopathy and conduction blocks
  • Nonspecific complaints such as fatigue and myalgia are common
• may manifest as multi-system involvement of apparently unrelated organs, e.g.
  • diabetes
  • visual impairment (Leber’s hereditary optic neuropathy)
  • sensorineural deafness
• Other organ system involvement is seen more often in children than in adult-onset disease, e.g.
  • Hepatic dysfunction
  • renal failure
  • haemopoeitic stem cell failure

Examination

• look for characteristic features of mitochondrial disease such as:
  • optic atrophy
  • ophthalmoparesis
  • hearing impairment
  • cardiac enlargement
  • neurological signs associated with muscle, brain and peripheral nerve involvement

Investigations

• Laboratory
  • FBC, UEC, LFTs, Coags, CaMgPO4, CK, lactate, NH3, ketoacids, glucose and glycated-Hb (identify multi-organ involvement and exclude other causes)
  • Urinalysis
  • muscle biopsy (histochemistry)
  • Lumbar puncture (mildly increased CSF protein and lactate may occur in mitochondrial diseases)
  • referral for genetic testing (e.g. Southern blot, PCR, RFLP analysis, mtDNA sequencing)
• Imaging
  • MRI brain
  • CXR
  • Echo
• Other tests
  • Lung function tests
  • EMG and nerve conduction studies
  • EEG (seizures or subacute encephalopathy)

Management

• No specific therapies, however numerous experimental therapies are under investigation
• Supportive care and monitoring, in addition to treating the underlying precipitant, are paramount in acute presentations
• Mitochondrial myopathy
  • avoid over-exertion and keep well hydrated
  • support for decreased mobility, falls risk and activities of daily living
  • treat rhabdomyolysis if indicated
• heart failure management if cardiomyopathy present
• permanent pacemaker may be required for conduction defects
• avoid aminoglycoside antibiotics, which may precipitate sensorineural deafness in some mitochondrial diseases

References and Links

LITFL

• CCC — Multi-Organ Dysfunction Syndrome (MODS)

FOAM and web resources

• FEMT — Mitochondria in Multi-Organ Failure – Mervyn Singer (2009)

Journal articles

• Anderson S, Bankier AT, Barrell BG. Sequence and organization of the human mitochondrial genome. Nature. 290(5806):457-65. 1981. [pubmed]
• Aslami H, Juffermans NP. Induction of a hypometabolic state during critical illness – a new concept in the ICU? Neth J Med. 2010 May;68(5):190-8. Review. PubMed PMID: 20508267. [Free Full Text]
• Ayoub IM, Radhakrishnan J, Gazmuri RJ. Targeting mitochondria for resuscitation from cardiac arrest. Crit Care Med. 2008 Nov;36(11 Suppl):S440-6. Review. PubMed PMID: 20449908; PubMed Central PMCID: PMC2865162.
• Chinnery PF. Mitochondrial disease in adults: what’s old and what’s new? EMBO molecular medicine. 7(12):1503-12. 2015. [pubmed] [free full text]
• Fink MP. Bench-to-bedside review: Cytopathic hypoxia. Crit Care. 2002 Dec;6(6):491-9. Epub 2002 Sep 12. Review. PubMed PMID: 12493070; PubMed Central PMCID: PMC153437.
• Kozlov AV, Bahrami S, Calzia E, Dungel P, Gille L, Kuznetsov AV, Troppmair J. Mitochondrial dysfunction and biogenesis: do ICU patients die from mitochondrial failure? Ann Intensive Care. 2011 Sep 26;1(1):41. doi: 10.1186/2110-5820-1-41. PubMed PMID: 21942988; PubMed Central PMCID: PMC3224479.
• Margulis L. Genetic and evolutionary consequences of symbiosis. Experimental parasitology. 39(2):277-349. 1976. [pubmed]
• McFarland R, Turnbull DM. Batteries not included: diagnosis and management of mitochondrial disease. Journal of internal medicine. 265(2):210-28. 2009. [pubmed] [free full text]
• Mongardon N, Dyson A, Singer M. Is MOF an outcome parameter or a transient, adaptive state in critical illness? Curr Opin Crit Care. 2009 Oct;15(5):431-6. doi: 10.1097/MCC.0b013e3283307a3b. Review. PubMed PMID: 19617821; PubMed Central PMCID: PMC2859600.
• Muravchick S, Levy RJ. Clinical implications of mitochondrial dysfunction. Anesthesiology. 2006 Oct;105(4):819-37. Review. PubMed PMID: 17006082. [Free Full Text]
• Protti A, Singer M. Bench-to-bedside review: potential strategies to protect or reverse mitochondrial dysfunction in sepsis-induced organ failure. Crit Care. 2006;10(5):228. Review. PubMed PMID: 16953900; PubMed Central PMCID:PMC1751057.
• Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence. 5(1):66-72. 2014. [pubmed] [free full text]
• Viscomi C, Bottani E, Zeviani M. Emerging concepts in the therapy of mitochondrial disease. Biochimica et biophysica acta. 1847(6-7):544-57. 2015. [pubmed] [free full text]