The clinical spectrum of mitochondrial diseases has expanded dramatically in the last decade. Abnormalities of mitochondrial function are now thought to participate in a number of common adult diseases, ranging from exercise intolerance to aging. This review outlines the common presentations of mitochondrial disease in ICUs and in the outpatient setting and discusses current diagnostic and therapeutic options as they pertain to the pulmonary and critical-care physician.

Theodur Leber unknowingly described the first mitochondrial disease in his description of adult-onset blindness in 1871.1 Luft’s disease, a disease characterized in 1962 with hypermetabolism and elevated core temperature, was the first disease proposed to have a mitochondrial origin.2 However, it was not until 1989 that the genetic bases for these diseases was discovered and their mitochondrial origin confirmed. Over the subsequent 11 years, there has been tremendous progress in understanding the genetics of mitochondrial disease, with > 200 mutations of the mitochondrial genome having been described.1 As knowledge has grown about these diseases, the clinical spectrum has expanded dramatically. Diseases with subtle clinical manifestations are now being described and relatively common diseases, such as Alzheimer’s dementia345 and Parkinson’s disease,46 are being investigated for mitochondrial involvement. Within the expanding spectrum of clinically significant diseases are common problems that present to the pulmonologist and intensivist, including unexplained dyspnea and exercise intolerance, respiratory failure, inability to wean from mechanical ventilation, and persistent lactic acidosis.

Mitochondrial dysfunction is devastating to the overall function of an organism. As the organelle responsible for energy production, pathologic changes in the mitochondria deprive cells of the adenosine triphosphate (ATP) that is essential for cellular functioning. Cells with high metabolic rates, such as those in the heart, brain, and skeletal muscle, are particularly vulnerable. Deprivation of ATP also facilitates alternative metabolic pathways, resulting in the accumulation of metabolic byproducts, such as lactate, which may be harmful to the organism.

Recognition of mitochondrial diseases requires an understanding of their common signs and symptoms as well as a basic understanding of mitochondrial biochemistry and genetics. The diseases are not always severe or life-threatening, and multiple organ systems do not need to be obviously involved. Skeletal muscle, the retina, or the pancreas may be the only organs affected. Diseases may present in the early and later years of life. DNA mutations with associated defects in mitochondrial function can be inherited with maternal, autosomal-dominant, or autosomal-recessive patterns, can occur spontaneously, or can be acquired as a result of environmental exposure or drug exposure. These mutations may be transient or persistent, or even may accumulate in the mitochondrial genome over a lifetime.

Several excellent reviews have summarized common clinical syndromes and the large and expanding number of mitochondrial DNA (mtDNA) mutations that are implicated in disease pathogenesis. This review will focus on the presentation of mitochondrial disease to the pulmonary and critical-care physician and will discuss, in terms of pathophysiology, the relevant clinical features, strengths, and weaknesses of diagnostic tests and the available therapeutic options.