Learning Objectives

• Understand the pathophysiology of oxidative phosphorylation failure.
• Identify tissues most vulnerable to mitochondrial dysfunction.
• Distinguish between MELAS, MERRF, and Leber Hereditary Optic Neuropathy.
• Recognize classic histologic findings like ragged red fibers and crystalline inclusions.

1. Pathophysiology and Tissue Vulnerability

Mitochondrial diseases arise from failures in oxidative phosphorylation. Because mitochondria are inherited maternally, these disorders follow a mitochondrial inheritance pattern, often complicated by heteroplasmy.

• High-Energy Demand: Tissues that require the most ATP are preferentially affected. This primarily includes the Central Nervous System (CNS) and skeletal muscle.

2. Mitochondrial Myopathies

These disorders are characterized by muscle weakness and neurological symptoms. Diagnosis is often heavily reliant on specific microscopic findings.

• MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes.
• MERRF: Myoclonic Epilepsy with Ragged Red Fibers.
• Histology (Light Microscopy): Ragged red fibers appear due to the compensatory proliferation of dysfunctional mitochondria under the sarcolemma.
• Histology (Electron Microscopy): Shows characteristic mitochondrial crystalline inclusions (parking lot inclusions).

3. Leber Hereditary Optic Neuropathy (LHON)

A specific mitochondrial disorder targeting the visual system due to mutations in Complex I of the Electron Transport Chain (ETC).

• Clinical Presentation: Subacute, painless, bilateral vision loss typically occurring in teens or young adults (males > females).
• Mechanism: Neuronal death in the retina and optic nerve.
• Associated Findings: May include tremors or a “multiple sclerosis-like” neurological illness.

Activity