Question

Cancer uses aerobic glycolysis to provide intermediates for cell division. Find a total of five mutations in any of the following processes: glycolysis/gluconeogenesis, cellular respiration (citric acid cycle, ETC and ATPase) or other processes that promote aerobic glycolysis. What is the normal function of the gene product (enzymes or regulators), how does the mutation promote aerobic glycolysis and if known, which type of cancer(s) do you see the mutation?

Answer 1

Q) CANCER USES AEROBIC GLYCOLYSIS TO PROVIDE INTERMEDIATES FOE CELL DIVISION. FIND TOTAL OF FIVE MUTATIONS IN ANY OF THE FOLLOWING PROCESSES: GLYCPLYSIS/GLUCONEOGENESIS, CELLULAR RESPIRATION (CITRIC ACID CYCLE,ETC AND ATPASE) OR OTHER PROCESS THAT PROMOTE AEROBIC GLYCOSIS. WHT IS THE NORMAL FUNCTION OF THE GENE PRODUCT (ENZYME OR REGULATOR), HOW DOES THE MUTATION PROMOTE AEROBIC GLYCOLYSIS AND IF KNOWN ,WHICH TYPE OF CANCER DO YOU SEE THE MUTATION.

Ans) CELLULAR RESPIRATION

Mitochondria are essential double-membraned subcellular organelles, present in all nucleated mammalian cells. Their primary function is to support aerobic respiration and produce, by oxidative phosphorylation (OXPHOS), the bulk of cellular ATP . The OXPHOS machinery is made up of over 80 different polypeptides, organised into five transmembrane complexes. Electrons, resulting from oxidation of fat and carbohydrates, are shuttled to oxygen along the first four respiratory chain (RC) complexes (CI–CIV), producing water, and providing the energy necessary to pump protons across the inner membrane (IMM) from the matrix to the intermembrane space. The electrochemical gradient thus created enables the fifth RC complex, ATP synthase, to phosphorylate ADP forming ATP. In addition to OXPHOS metabolism, mitochondria control cytosolic calcium concentration  and regulate apoptotic cell death . They are the major source of endogenous reactive oxygen species (ROS)  and they host other important biochemical pathways, including the tricarboxylic acid (TCA) cycle and parts of the urea cycle . Furthermore, these organelles are central to iron–sulphur cluster biogenesis, the only entirely conserved function of eukaryote mitochondria.

1). mtDNA mutations

**) Point mutations

MtDNA point mutations are usually maternally inherited. They may occur within protein, tRNA, or rRNA genes. However, more than half of disease-related point mutations reported are located within mt-tRNA genes. Phenotypically, point mutations in mitochondrial protein-coding genes specifically affect the function of the RC complex to which the corresponding protein belongs, whereas mt-tRNA mutations may impair overall mitochondrial translation by reducing the availability of functional mt-tRNAs.

Point mutations are mostly heteroplasmic, displaying considerable clinical heterogeneity, and are considered highly recessive. However, an increasing number of pathogenic homoplasmic mutations, often affecting just a single tissue and characterised by incomplete penetrance, are being recognised . Given the high mutational rate of the mitochondrial genome and the presence of numerous family- or population-specific polymorphisms, the distinction between neutral mtDNA variant and disease-causing mutation can often be difficult. To complicate matters further, a dominant mt-tRNA mutation, m.5545C > T in the MT-TW gene, was recently reported with levels of mutation at < 25% in clinically affected tissues . Also, it has been frequently recognised that certain nucleotide changes that are not pathogenic per se may modulate the effects of deleterious mtDNA mutations .

**) MtDNA rearrangements

The majority of mtDNA rearrangement mutations are large-scale deletions, which vary in size from 1.3 to 8 kb and span several genes . Single mtDNA deletions occur sporadically early in development, and the identical deletion is present in all cells within affected tissues . The occurrence of multiple mtDNA deletions of varying lengths in affected tissues may be due to inherited mutations in nuclear genes, whose products are involved in mtDNA maintenance and replication (e.g., POLG and PEO1 encoding Twinkle) and mitochondrial nucleotide metabolism (e.g., SLC25A4) . An exponential accumulation of multiple mtDNA deletions has also been reported in aged postmitotic tissues and individuals with neurodegenerative diseases .

2) A gene product is the biochemical material, either RNA or protein, resulting from expression of a gene. A measurement of the amount of gene product is sometimes used to infer how active a gene is. Abnormal amounts of gene product can be correlated with disease-causing alleles, such as the overactivity of oncogenes which can cause cancer.^[1][2] A gene is defined as "a hereditary unit of DNA that is required to produce a functional product".^[3] Regulatory elements include:

• Promoter region
• TATA box
• Polyadenylation sequences
• Enhancers