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Dysfunctional Mitochondria - Types and Causes

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Mitochondria is essential for ocular tissue function. Mitochondrial dysfunction is caused by several disorders leading to visual problems.

Medically reviewed by

Dr. Asha Juliet Barboza

Published At February 10, 2023
Reviewed AtMarch 27, 2023


Mitochondria is one of the most important organelles of the cell. It is responsible for the cell's energy production and is known as its powerhouse. The number and densities of mitochondria in a cell vary according to their type and function. Aging, acute and chronic diseases can impair the function of the mitochondria.

Mitochondria is responsible for maintaining the metabolism of retinal epithelium and neural tissues of the retina. Any change in mitochondria's functioning leads to the ocular tissues' degradation. Thus understanding the dysfunctional changes in the mitochondria due to various reasons is essential to study ocular pathologies.

What Is the Function of Mitochondria?

Mitochondria are a double membrane-bound organelle of the eukaryotic cell. It produces ATP (Adenosine triphosphate) through the aerobic respiration process. These molecules function as power production units and help in various cellular functions. Besides this, other functions of mitochondria are regulating the cellular life cycle, prompting cellular growth and multiplication, the production of heat, and calcium absorption.

The number of mitochondria present in a human cell depends upon the cell type and its functions. Red blood cells do not have mitochondria. On the other hand, cells with a high energy requirement, like liver cells or muscle cells, have more mitochondria. The retina is a tissue with high energy requirements. Photoreceptor cells, retinal pigment epithelium, and retinal ganglion cells are highly dependent on mitochondria for cellular metabolism, which is why dysfunction in the mitochondrial function affects ocular tissues very much.

What Is the Cause of Dysfunctional Mitochondria?

Several factors can cause mitochondrial dysfunction, such as:

  • Age-Related Changes: Oxidative damage due to aging.

  • Primary Mitochondrial Dysfunction: These are inherited disorders caused by the abnormal cellular function of mitochondria.

  • Secondary Mitochondrial Dysfunction: These are caused by systemic disorders that disrupt cellular organelles' normal functioning.

What Are the Age-Related Changes?

With increasing age, the accumulation of reactive oxygen species (oxygen contains molecules that react with other molecules) causes oxidative damage to the mitochondria. Along with this, the volume and functionality of the mitochondria decrease. Age-related macular degeneration is caused by impairment of mitochondrial function. This is characterized by:

  • Degeneration of the nerve of the retina.

  • Atrophy (loss of cells) of the photoreceptor cells and retinal pigmented epithelium cells.

  • Presence of yellow spots (drusen) or hyper-pigmented areas in the retina.

  • Formation of newly formed blood vessels.

The changes seen in mitochondrial functions are due to the following:

  • According to the oxidative stress hypothesis, the accumulation of oxidative substances causes damage to the proteins, lipids, and DNAs (deoxyribonucleic acid). These altered protein expressions are responsible for the improper functioning of the mitochondria.

  • Loss of cristae, alterations in the mitochondrial membrane, and changes in mtDNA functioning are responsible for dysfunctional mitochondria.

What Is Primary Mitochondrial Dysfunction?

This is caused by abnormal gene functioning in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Mitochondrial DNA and nuclear DNA (nDNA) are responsible for protein synthesis, which is essential for the functioning of the mitochondria. Dysfunctional mitochondria cause different abnormalities with ocular involvement. The mutation of the GTPase (guanosine triphosphate) nuclear gene, OPA1 (optic atrophy 1), is responsible for this. They are:

1. Dominant Optic Atrophy: This is a genetic disorder affecting retinal ganglion cells (RGC) and the nerve fiber layer of the retina. It affects 1 in every 35000 persons. The clinical manifestations are:

  • Loss of vision.

  • Thinning of the neuroretinal rim of the optic nerve.

  • Abnormal shape of the optic nerve head, disc, and dislocation.

2. Leber Hereditary Optic Neuropathy (LHON): This is also a genetic disorder characterized by sequential loss of vision over a few months in one eye. Three-point mutations in mitochondrial DNA (mtDNA) are G11778A mutation in the ND4 gene, G3460A mutation in ND1gene, and T14484C mutation in the ND6 gene responsible for this condition. Clinical features are:

  • Thickening of the retinal nerve fiber layers.

  • Retinal ganglion cell loss.

  • Decreased red-green discrimination.

3. Chronic Progressive External Ophthalmoplegia (CPEO): This is a complex condition characterized by impaired function of the extraocular muscles and double vision. This is caused by the deletion of single mitochondrial DNA (mtDNA). TYMP (thymidine phosphorylase), ANT1 (adenine nucleotide translocase type1), PEO1 (progressive external ophthalmoplegia 1), POLG (DNA polymerase subunit gamma-1), POLG2 (DNA polymerase subunit gamma-2), and OPA1 are the genes responsible for these conditions. Clinical manifestations are:

  • Bilateral ptosis or drooping of the upper eyelids.

  • Reduced thickness of the outer retinal layer.

  • Thinning of the optic nerve head and optic rim.

4. Pigmentary Retinopathy: This is a nonspecific finding related to several genetic disorders like Leigh syndrome (a degenerative disorder involving the basal ganglia and brainstem), mitochondrial encephalomyopathy lactic acidosis, and stroke (MELAS) (a congenital condition that affects nerves and muscles), Kearns-Sayre Syndrome (KSS) (a neuromuscular disorder characterized by eye muscles).

5. Ocular Dysfunction: Ocular dysfunction caused by primary mitochondrial dysfunction is difficult to treat. Gene replacement therapy or administration of pluripotent cells can be helpful in such cases.

What Is Secondary Mitochondrial Dysfunction?

This is a multifactorial entity. Unlike primary mitochondrial dysfunctions, the genes responsible for this condition do not affect oxidative phosphorylation. This may also be caused by factors like mitochondrial toxins (cigarette smoke, metals) and drugs (Tetracycline, valproate), which are responsible for oxidative stress in the mitochondria.

1) Diabetic Retinopathy: An often encountered conditions associated with impaired mitochondrial function is diabetes. It can be said as one of the leading causes of vision loss in the adult population. The clinical changes in conditions are:

  • Occlusion of the retinal blood vessels.

  • Diabetic macular edema or accumulating fluid within the retina due to capillary leakage.

  • Formation of new blood vessels.

  • Vitreous hemorrhage or the presence of blood in the vitreous humor.

The pathological factor which is responsible for dysfunctional mitochondria is oxidative stress. Decreased level of intracellular antioxidants leads to the accumulation of reactive oxygen species. Moreover, high content of polyunsaturated fatty acids, high oxygen uptake, and glucose oxidation in diabetic conditions also trigger oxidative stress. This leads to damage to the mitochondrial membrane and the destruction of mitochondrial DNA (mtDNA).

2) Glaucoma: Glaucoma is a neurodegenerative disorder characterized by the death of retinal ganglion cells and elevated eye pressure. Elevated intraocular pressure leads to the accumulation of reactive oxygen species. Optic nerve fibers reached with mitochondria are damaged due to elevated pressure. Also, the presence of reactive oxygen species is responsible for the damage to the mitochondria.

Conservative and surgical methods can treat such cases. The antioxidant can be useful to promote the function of the mitochondria.


Mitochondrial functions are very much related to ophthalmic health. Dysfunction in the mitochondrial functions is responsible for serious complications like nerve damage and blindness. Genetic factors are associated with these conditions, so treatment in such cases is often difficult. Early diagnosis of such conditions can help plan proper treatment procedures.

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Dr. Asha Juliet Barboza
Dr. Asha Juliet Barboza

Ophthalmology (Eye Care)


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