Defects often affect the operation of the mitochondria and multiple tissues more severely, leading to multi-system diseases.

[citation needed] An outstanding question and area of research is whether ATP depletion or reactive oxygen species are in fact responsible for the observed phenotypic consequences.

They may also be the result of acquired mitochondrial dysfunction due to adverse effects of drugs, infections, or other environmental causes.

As mtDNA is copied when mitochondria proliferate, they can accumulate random mutations, a phenomenon called heteroplasmy.

Mitochondrial disease may become clinically apparent once the number of affected mitochondria reaches a certain level; this phenomenon is called "threshold expression".

Defects in nuclear-encoded mitochondrial genes are associated with hundreds of clinical disease phenotypes including anemia, dementia, hypertension, lymphoma, retinopathy, seizures, and neurodevelopmental disorders.

[21] A study by Yale University researchers (published in the February 12, 2004, issue of the New England Journal of Medicine) explored the role of mitochondria in insulin resistance among the offspring of patients with type 2 diabetes.

[22] Other studies have shown that the mechanism may involve the interruption of the mitochondrial signaling process in body cells (intramyocellular lipids).

A study conducted at the Pennington Biomedical Research Center in Baton Rouge, Louisiana[23] showed that this, in turn, partially disables the genes that produce mitochondria.

Using genetic engineering in attempts to produce babies free of mitochondrial disease is controversial in some circles and raises important ethical issues.

[40] In June 2013, the United Kingdom government agreed to develop legislation that would legalize the 'three-person IVF' procedure as a treatment to fix or eliminate mitochondrial diseases that are passed on from mother to child.

Research and clinical applications of MRT were overseen by laws made by federal and state governments.

The committee's report, released in July 2011, recommended the existing legislation remain unchanged Currently, human clinical trials are underway at GenSight Biologics (ClinicalTrials.gov # NCT02064569) and the University of Miami (ClinicalTrials.gov # NCT02161380) to examine the safety and efficacy of mitochondrial gene therapy in Leber's hereditary optic neuropathy.