Because of the complex ways in which mitochondrial and nuclear DNA "communicate" and interact, even seemingly simple inheritance is hard to diagnose.

It was originally incorrectly believed that the mitochondrial genome contained only 13 protein-coding genes, all of them encoding proteins of the electron transport chain.

However, in 2001, a 14th biologically active protein called humanin was discovered, and was found to be encoded by the mitochondrial gene MT-RNR2 which also encodes part of the mitochondrial ribosome (made out of RNA): Unlike the other proteins, humanin does not remain in the mitochondria, and interacts with the rest of the cell and cellular receptors.

The entire molecule is regulated by only one regulatory region which contains the origins of replication of both heavy and light strands.

A generally accepted hypothesis is that mitochondria originated as an aerobic prokaryote in a symbiotic relationship within an anaerobic eukaryote.

Mitochondrial replication is controlled by nuclear genes and is specifically suited to make as many mitochondria as that particular cell needs at the time.

The actual molecular events that are involved in initiation are unknown, but these factors make up the basal transcription machinery and have been shown to function in vitro.

[citation needed] The Mitochondrial DNA Polymerase (Pol gamma, encoded by the POLG gene) is used in the copying of mtDNA during replication.

Mitochondria sometimes form large matrices in which fusion, fission, and protein exchanges are constantly occurring.

[citation needed] Mitochondrial DNA is susceptible to damage from free oxygen radicals from mistakes that occur during the production of ATP through the electron transport chain.

These radicals can damage mtDNA molecules or change them, making it hard for mitochondrial polymerase to replicate them.

Recent evidence has suggested that mitochondria have enzymes that proofread mtDNA and fix mutations that may occur due to free radicals.

It is believed that a DNA recombinase found in mammalian cells is also involved in a repairing recombination process.

Despite the fact that the loci for some of these mutations have been found on human chromosomes, specific genes and proteins involved have not yet been isolated.

Indirect mutations are most often caused by radicals created by defective proteins made from nuclear DNA.

[citation needed] In total, the mitochondrion hosts about 3000 different types of proteins, but only about 13 of them are coded on the mitochondrial DNA.

This means most of the genetic information coding for the protein makeup of mitochondria is in chromosomal DNA and is involved in processes other than ATP synthesis.

This increases the chances that a mutation that will affect a mitochondrion will occur in chromosomal DNA, which is inherited in a Mendelian pattern.

This almost patient-specific characterization of mitochondrial diseases (see Personalized medicine) makes them very hard to accurately recognize, diagnose and trace.

Some diseases are observable at or even before birth (many causing death) while others do not show themselves until late adulthood (late-onset disorders).

[26] Many researchers believe that mtDNA is better suited to identification of older skeletal remains than nuclear DNA because the greater number of copies of mtDNA per cell increases the chance of obtaining a useful sample, and because a match with a living relative is possible even if numerous maternal generations separate the two.

[28] Similarly to identify Emperor Nicholas II remains his mitochondrial DNA was compared with that of James Carnegie, 3rd Duke of Fife, whose maternal great-grandmother Alexandra of Denmark (Queen Alexandra) was sister of Nicholas II mother Dagmar of Denmark (Empress Maria Feodorovna).