Mitochondria

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Introduction

Electron micrograph of mitochondria.

Originally discovered in muscle by Kölliker in 1857, mitochondria are the "powerhouses" of the cell and the location where respiration occurs at the cellular level. These cytoplasmic organelles also contain their own DNA (mitochondrial DNA or mtDNA) that has been originally inherited only from the oocyte (maternal inheritance). The spermatozoa (paternal) mitochondria, required for energy for fertilization motility, can enter the oocyte but are generally destroyed during the first mitotic cell divisions. This pattern of inheritance has important implications for a variety of mitochondrial associated diseases, usually occurring in tissues requiring lots of energy (muscle, brain). Recent experiments have employed swapping maternal mitochondrial DNA in mammalian oocytes.


Swapping mitochondrial DNA mammalian oocytes

Swapping mitochondrial DNA mammalian oocytes[1]


Links: Genetics | Assisted Reproductive Technology | Cell Biology - Mitochondria


Some Recent Findings

Spermatozoa Mitochondria in Early Mouse Embryos[2]
  • Unique insights into maternal mitochondrial inheritance in mice.[2] "In animals, mtDNA is always transmitted through the female and this is termed "maternal inheritance." Recently, autophagy was reported to be involved in maternal inheritance by elimination of paternal mitochondria and mtDNA in Caenorhabditis elegant. ...However, by using two transgenic mouse strains, one bearing GFP-labeled autophagosomes and the other bearing red fluorescent protein-labeled mitochondria, we demonstrated that autophagy did not participate in the postfertilization elimination of sperm mitochondria in mice. Based on these results, we conclude that, in mice, maternal inheritance of mtDNA is not an active process of sperm mitochondrial and mtDNA elimination achieved through autophagy in early embryos, but may be a passive process as a result of prefertilization sperm mtDNA elimination and uneven mitochondrial distribution in embryos."
  • Recurrent tissue-specific mtDNA mutations are common in humans[3] "Mitochondrial DNA (mtDNA) variation can affect phenotypic variation; therefore, knowing its distribution within and among individuals is of importance to understanding many human diseases. Intra-individual mtDNA variation (heteroplasmy) has been generally assumed to be random. We used massively parallel sequencing to assess heteroplasmy across ten tissues and demonstrate that in unrelated individuals there are tissue-specific, recurrent mutations. Certain tissues, notably kidney, liver and skeletal muscle, displayed the identical recurrent mutations that were undetectable in other tissues in the same individuals. ...The most parsimonious explanation of the data is that these frequently repeated mutations experience tissue-specific positive selection, probably through replication advantage."
  • Heteroplasmy of mouse mtDNA is genetically unstable and results in altered behavior and cognition[4] "Maternal inheritance of mtDNA is the rule in most animals, but the reasons for this pattern remain unclear. To investigate the consequence of overriding uniparental inheritance, we generated mice containing an admixture (heteroplasmy) of NZB and 129S6 mtDNAs in the presence of a congenic C57BL/6J nuclear background. Analysis of the segregation of the two mtDNAs across subsequent maternal generations revealed that proportion of NZB mtDNA was preferentially reduced. Ultimately, this segregation process produced NZB-129 heteroplasmic mice and their NZB or 129 mtDNA homoplasmic counterparts. Phenotypic comparison of these three mtDNA lines demonstrated that the NZB-129 heteroplasmic mice, but neither homoplasmic counterpart, had reduced activity, food intake, respiratory exchange ratio; accentuated stress response; and cognitive impairment. Therefore, admixture of two normal but different mouse mtDNAs can be genetically unstable and can produce adverse physiological effects, factors that may explain the advantage of uniparental inheritance of mtDNA."

Maternal Inheritance

Most animals

  • Oocyte mitochondria (maternal) are the only mitochondria inherited. (see genetics below)
    • maternal mitochondrial genome inheritance.
  • Spermatozoa mitochondria (paternal) can enter oocyte at fertilisation.
    • Male spermatozoa are destroyed early in embryonic development (mechanism not yet elucidated)
    • worm - (C. elegans) suggest ubiquitination occurs followed by autophagy.[5]
    • mouse - suggest a more passive process, prefertilization sperm mtDNA elimination and uneven mitochondrial distribution in embryos.[2]


Paternal Mitochondria

Spermatozoa organelles, including mitochondria, are destroyed in some species by the process of autophagy following fertilisation.[6]

Recent studies in mice suggest that additional mechanisms may be used in paternal mitochondrial elimination.[2]

Mouse spermatozoa mito movie icon.jpg
 ‎‎Male Mitochondria
Page | Play
Links: Spermatozoa Development

History Mitochodria

1857 Kölliker discovers mitochondria in muscle

1929 Karl Lohmann discovered ATP

1940s and 1950s ATP is formed in cell respiration in mitochondria and photosynthesis in chloroplasts of plants

1960 Efraim Racker and co-workers isolated, from mitochondria, the enzyme "F o F 1 ATPase" now call ATP synthase

1963 There’s DNA in those organelles DNA is directly visualized in first chloroplasts and then mitochondria, from the JCB Archive.


1992 Wallace identified degenerative disease caused by mtDNA mutations

1997 Nobel Prize in Chemistry - The three laureates have performed pioneering work on enzymes that participate in the conversion of the "high-energy" compound adenosine triphosphate (ATP).

  • Paul D. Boyer and John E. Walker "for their elucidation of the enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP)"
  • Jens C. Skou "for the first discovery of an ion-transporting enzyme, Na+, K+ -ATPase

Evolution Mitochondria

  • primitive Eubacterium
  • symbiotic relationship with eukaryotic cell
    • circular DNA
    • see antibiotic-induced deafness due to similarity of mitochondrial and bacterial ribosomes
  • genes transferred to nucleus
  • mitochondrial genome bp
    • 366,924 Arabidopsis
    • 16,569 Human
    • 5966 Plasmodium

Mitochondrial Genome

Eukaryotic mitochondrial genomes
  • In humans this genome is maternally inherited.
  • Exists as multiple copies within the matrix of each mitochondrion within the cytoplasm of cells.
  • In 1981 the human mitochondrial genome was sequenced.
  • The genome is a small circular DNA molecule 16,568 bp in length containing 37 genes.
    • 24 genes specify RNA molecules involved in protein synthesis (22 transfer RNAs (tRNA) and 2 ribosomal RNAs (rRNA))
    • 13 genes encode proteins required for the biochemical reactions that make up respiration.


Links: 16569 bp Homo sapiens mitochondrion | Mitochondrial DNA Deletion Syndromes


Spindle Transfer

(ST) An Assisted Reproductive Technology term referring to the transfer of the metaphase II-arrested (MII) spindle-chromosomal complex isolated as a karyoplast from a donor oocyte to the cytoplasm of a second recipient oocyte. The term cytoplast refers to the enucleated recipient oocyte. This technique has been suggested as a clinical solution to mitochondrial inherited disorders.


Swapping mitochondrial DNA mammalian oocytes.jpg

Swapping mitochondrial DNA mammalian oocytes[1]

Links: Assisted Reproductive Technology | Mitochondrial DNA Deletion Syndromes | PMID 20539289

Mitochondria Components

Outer Membrane

  • porin - membrane channel, allows ions and metabolites into the mitochondria (<5000 daltons)

Intermembrane Space

  • similar to the cytosol with respect to the small molecules it contains
  • also enzymes that use ATP

Inner Membrane

  • cardiolipin - phospholipid, makes membrane impermeable to ions (unique to mitochondria inner membrane)
  • transport proteins - permeable to molecules required in the matrix

Cristae

  • increase inner membrane surface area
    • tubular, vesicular or flat cristae
  • Adenosine triphosphate (ATP) synthase
  • respiratory electron transfer chain proteins
  • transport proteins


Links: Model - inner boundary membrane and cristae membranes

Matrix

  • metabolic enzymes of citric acid cycle (=Krebs) (100s of enzymes) (MH- do not need to know biochemical details of this cycle)
  • genetic material DNA, tRNA, ribosomes

Mitochondria DNA

Eukaryotic mitochondrial genomes
  • double stranded circular DNA (mitoDNA. mtDNA)
  • 1981 complete human sequence (16,569 nucleotides)
  • 37 genes
    • encodes 13 polypeptides involved in oxidative phosphorylation
    • remaining genes transfer RNA (tRNA) and ribosomal RNA (rRNA)
  • multiple copies within the matrix
  • maternally inherited
  • remainder encoded by nuclear DNA
  • proteins made in cytosol and imported into mitochondria



Links: Home Reference - Mitochondrial DNA

Mitochondria Protein Synthesis

Many mitochondrial proteins are encoded by nuclear DNA

  • synthesis begins in the cell cytoplasm
  • imported into the mitochondria
    • targeting similar to signal sequence for RER
  • once in matrix signal sequence is cleaved (by Hsp70)
    • protein then folds (by Hsp60)
  • proteins for mitochondrial membrane or intermembranous space
  • additional signal following matrix localization

Mitochondrial targeting signal (MTS) - alternating amino acid pattern (amphipathic helix) with a few hydrophobic amino acids and a few plus-charged amino acids at the N terminus.


Links: Replication and preferential inheritance of hypersuppressive petite mitochondrial DNA | Home Reference - Mitochondrial DNA

Mitochondrial Disorders

There has been recent discussion on the use of specialised Assisted Reproductive Technology (ART) techniques to allow replacement of maternal mitochondria with genetic abnormalities with a healthy donor mitochondria.


Mitochondrial DNA disorder Description Prevalence Life expectancy/morbidity
Kearns–Sayre syndrome Progressive blindness and blocked heart Rare disease Onset before 15
Chronic progressive external opthalmoplegia (CPEO) Progressive wastage of eyelids, eyes and sometimes facial muscles Rare disease Onset in young adulthood
Pearson syndrome Anaemia, pancreatic failure, muscle wastage Very rare (less than 100 worldwide) Early death
Myopathy, encephalopathy, lactic acidosis and stroke (MELAS) Stroke like episodes; muscle spasm; early dementia Rare disease Death before 40
Myoclonic epilepsy and ragged-red fibres (MERFF) Epilepsy, hearing loss, lactic acidosis, short stature 1 in 400,000 across Europe Childhood onset
Neurogenic weakness, ataxia and retinitis pigmentosa (NARP) Muscle weakness, vision loss, learning disabilities Rare disease Onset in early childhood. Early death
Maternally inherited Leigh syndrome (MILS) Muscle weakness, heart and kidney failure, delayed development Very rare Onset in infancy. Death in early childhood
Maternally inherited diabetes and deafness (MIDD) Combination of all types of diabetes with deafness Rare disease Adult onset
Leber hereditary optic neuropathy (LHON) Rapid blindness 1 in 30,000 across Europe Range from early childhood to 70s
Myopathy and diabetes Covers forms of muscular dystrophy From infancy. Early death
Sensorineural hearing loss Covers a range of hearing loss through to deafness Common condition but rarely caused by mitochondrial disease Onset at any age
Exercise intolerance Range from lethargy to muscle wastage 1 in 8,000 but symptoms often combine with others Onset in early life
Fatal infantile encephalopathy
(Leigh syndrome) 		Brain and nervous system dysfunctions Very rare Onset in infancy. Death in early childhood
Links: Mitochondria | Genetic Abnormalities | Zygote
 Table based on Annex D, UK Mitochondrial Donation 2014.


Links: Assisted Reproductive Technology

References

  1. ↑ 1.0 1.1 <pubmed>19759608</pubmed>
  2. ↑ 2.0 2.1 2.2 2.3 <pubmed>23878233</pubmed>| Proc Natl Acad Sci U S A. Cite error: Invalid <ref> tag; name 'PMID23878233' defined multiple times with different content Cite error: Invalid <ref> tag; name 'PMID23878233' defined multiple times with different content Cite error: Invalid <ref> tag; name 'PMID23878233' defined multiple times with different content
  3. ↑ <pubmed>24244193</pubmed>
  4. ↑ <pubmed>23063123</pubmed>
  5. ↑ <pubmed>24528894</pubmed>
  6. ↑ <pubmed>22033522</pubmed>


Search PubMed

Search Pubmed: Mitochondria


Terms

  • maternal spindle transfer - (MST) An Assisted Reproductive Technology term. The “maternal spindle” is the group of maternal chromosomes within the oocyte, which are shaped in a spindle. The transfer technique involves removing the spindle from the mother’s oocyte before it is fertilised by the father’s spermatozoa. The spindle is then placed into a donor oocyte with healthy mitochondria, from which the donor’s spindle, and therefore her nuclear material, has been removed.
  • Pro-nuclear transfer - (PNT) An Assisted Reproductive Technology term. The pro-nucleus is the nucleus of either a spermatozoa or an oocyte during the process of fertilisation after the sperm enters the egg, but before they fuse. Transfer involves removing the pro-nuclei from a newly fertilized oocyte that has unhealthy mitochondria. The pro-nuclei are then transferred into a donated embryo, with healthy mitochondria, that has had its own, original pro-nuclei removed.


External Links

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Cite this page: Hill, M.A. (2024, May 4) Embryology Mitochondria. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Mitochondria

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© Dr Mark Hill 2024, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G
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