Lecture 12: Mitochondria (December 2024) PDF

LECTURE 12 (December 2024) Chapter 15. Mitochondria (end of the chapter) 15.8. Mitochondria, implications in pathology There are two categories of pathological processes in which mitochondria are involved: A. mitochondrial genetic diseases and B. Other pathological pro...

LECTURE 12 (December 2024) Chapter 15. Mitochondria (end of the chapter) 15.8. Mitochondria, implications in pathology There are two categories of pathological processes in which mitochondria are involved: A. mitochondrial genetic diseases and B. Other pathological processes. A. Mitochondrial genetic diseases Mitochondrial genetic diseases are caused by mutations in mitochondrial proteins, like components of the respiratory chain complexes (from I to V, with the fifth being the ATP-synthase complex). Since some of the polypeptide chains of these components are encoded by nuclear genes and others by mitochondrial DNA, mitochondrial diseases can result from mutations in either mitochondrial DNA or nuclear genes. In these diseases, mitochondria often appear enlarged but are inefficient at producing sufficient ATP for the cell. This dysfunction primarily affects muscles (often causing ptosis in the eyelid muscles) and the brain (frequent epileptic seizures). As a result, these genetic mitochondrial diseases are referred to as mitochondrial encephalomyopathies. The onset can occur at any age, from birth to adulthood. In some cases, other organs besides the muscles and brain, such as the liver, glands, and kidneys, may also be affected. In general, these diseases manifest from birth or childhood and are classified as mitochondrial cytopathies, while those that begin in adulthood are usually mitochondrial encephalomyopathies. The diagnosis is difficult, complex analyses are necessary, based on the dosage of plasma components (lactic acidosis frequently appears), and the study of mitochondria isolated from muscles (in laboratories specialized where it can analyse the components of the respiratory chain), and up to the sequencing analysis of mitochondrial DNA. It is important that the mitochondrial genes come only from the mother, due to the fact that during the fusion of the sperm with the ovule, only the head of the sperm (where the nucleus is located) is introduced into the ovule. The genetics of mitochondrial diseases is made more complicated by the fact that in the egg cell which has mutant mitochondrial DNA, this is not present in all the mitochondria, but it exists in the same cell and mitochondria with the normal DNA. Then, in the division of cells with mutant mitochondrial DNA, the mitochondria with this DNA are not distributed equally to the daughter cells (heteroplasmy). Hence the complexity of the forms that mitochondrial diseases take. Examples of mitochondrial genetic diseases: a) Leber disease (named after the person who described it, Leber’s Hereditary Optic Neuropathy – LHON): caused by point mutations in mtDNA – complex I defects of the mitochondrial respiratory chain. Is manifested by atrophy of the optic nerve, which could lead to blindness. The onset can occur at any age and might be brutal, with blindness occurring instantly or within a few days. It has been noted that among the most common factors that trigger the disease is exposure to carbon monoxide (CO), including smoking (actively or passively). b) MELAS syndrome is caused by mitochondrial DNA mutations and is characterized by mitochondrial encephalomyopathy, lactic acidosis and stroke episodes, hence the acronym MELAS. B. Other pathological processes in which mitochondria are involved Mitochondria are now justifiably recognized as being involved in all diseases. Since mitochondria provide most of the energy required by cells, a lack of sufficient energy support causes cellular dysfunction and disease. Additionally, mitochondrial DNA, unlike nuclear DNA which is protected by the cell envelope, is unprotected in the matrix and exposed to reactive oxygen species (ROS) such as free radicals and singlet oxygen. These ROS, generated in large amounts during redox reactions, can damage mitochondrial DNA and proteins, leading to cellular harm. ROS are now known to play a role in the pathogenesis of various diseases, including major causes of morbidity and mortality worldwide, such as cardiovascular diseases, neurodegenerative diseases, cancer, and diabetes. Finally, the involvement of mitochondria in the triggering of programmed cell death (apoptosis) has been proven (see the chapter on cell death). 1  Chapter 19. Central Dogma of Molecular Biology and the Medical Applications 19.1. What is Central dogma of molecular biology? The central dogma of molecular biology (CDMB), proposed by Francis Crick in 1958, describes the flow of genetic information, from DNA to messenger RNA (mRNA), to make a functional product - a protein: The CDMB has been described (with some differences between the two) for both eukaryotes and prokaryotes. In eukaryotes the genetic material is located mainly in the nucleus. The DNA replication and DNA transcription are performed into the nucleus; then, the messenger RNA molecule (mRNA) passes through the nuclear pores into the cytoplasm, where proteins are synthesized by ribosomes (translation). Prokaryotic cells don’t have nucleus and all these processes occur in cytoplasm. 19.2. The genetic material Genetic material is the material support of heredity and it consists of DNA in both eukaryotic and prokaryotic cells. a) In eukaryotes there are linear DNA molecules in chromosomes and circular DNA molecules in mitochondria; chloroplasts in plants also contain circular DNA molecules. DNA contains genes in which the genetic information is encoded in the nucleotide sequence. The total number of chromosomal genes represents the genome. The human nuclear genome contains approximately 21,000 genes. The content of the human genome is commonly divided into coding and non-coding DNA sequences. Coding DNA is defined as those sequences that can be transcribed into mRNA and translated into proteins during the human life cycle; these sequences occupy only a small fraction of the genome (