Treatment of Mitochondrial Cytopathies

, MD and , Section of Pediatric Neurology, Cleveland Clinic Foundation, Cleveland, Ohio. 

Semin Neurol. 2001;21(3) 

In This Article

Abstract and Introduction

Mitochondrial cytopathies are clinically and biochemically heterogeneous disorders affecting energy production. Because of the diverse symptoms spanning organ systems, the large number of biochemical and genetic defects, and an unpredictable clinical course, there are limited data regarding proven effective therapies. In general, treatments for mitochondrial cytopathies are intended to augment energy production as well as reduce the production of free radicals and other toxic metabolites that further limit the generation of cellular energy. Theoretically, treatment can be aimed at increasing respiratory chain activity by supplementing relative deficiencies of cofactors required for proper functioning. Possible strategies to consider may include dietary management, supplemental vitamins and cofactors, and/or specific medications aimed at a particular symptom.
Objectives. On completion of this article the reader will be able to summarize the current treatment options for patients with mitochondrial disorders.
Accreditation. The Indiana University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Credit. The Indiana University School of Medicine designates this educational activity for a maximum of 1.0 hours in category one credit toward the AMA Physicians Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.
Disclosure. Statements have been obtained regarding the authors' relationships with financial supporters of this activity. There is no apparent conflict of interest related to the context of participation of the authors of this article.


Understanding therapy for those with mitochondrial disease requires knowledge of the underlying pathogenesis. The term mitochondrial cytopathies refer to the human illnesses resulting from primary and secondary mitochondrial dysfunction. The mitochondria are responsible for energy production, which is generated in the form of adenosine triphosphate (ATP). A series of well-orchestrated chemical reactions culminate in the phosphorylation of adenosine diphosphate (ADP) by the process of oxidative phosphorylation (OXPHOS), which occurs in the five enzyme complexes imbedded in the inner mitochondrial membrane that comprise the electron transport chain (ETC). In addition to energy generation, the mitochondria also play pivotal roles in both the generation of free radicals and the process of apoptosis, or "programmed" cell death. Although therapy primarily focuses on improving energy production, the other functions of the mitochondria may be important in future consideration of treatment options.

Physicians caring for those with mitochondrial cytopathies are faced with a new challenge. The current practice of specialized medical care stratifies physicians and their patients by diseases of organs and organ systems. Although dysfunction of one organ can affect another adjacent organ, such as congestive heart failure causing pulmonary edema, it is usually observed that successful treatment of the primary disease will result in improvement of other organ dysfunction. Mitochondrial cytopathies are not diseases of particular organs, but a disease or disease state of an organelle. The consequences of faulty ATP production are more severe in those tissues with a high-energy requirement, which may impact on the function of only a few selected organs or cause widespread damage affecting most organ systems. Successful management of an ill person with a mitochondrial cytopathy requires the orchestrated efforts of a primary care physician, medical specialists, and a physician comfortable with the intricacies of mitochondrial disorders. Because of the diverse nature of affected organ systems, evaluation of any given therapy can be quite a challenge.

In spite of the multiplicity of clinical presentations and underlying pathophysiology, there are several well-described phenotypes that have been instrumental in the evolution of our knowledge of mitochondrial diseases. Kearns-Sayre syndrome (KSS), typically seen in conjunction with a defect in metabolism of coenzyme Q10, usually presents with ophthalmoplegia, retinopathy, cardiac conduction defects, ataxia, and short stature. Episodic vomiting, lactic acidosis, myopathy, seizures, strokelike events, and short stature tend to characterize mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). Myoclonic epilepsy with ragged-red fibers (MERRF) is distinguished by the presence of severe myoclonus, epilepsy, ataxia, and myopathy with ragged-red fibers. Leber hereditary optic neuropathy (LHON) is characterized primarily by blindness in men. Respiratory irregularities, myopathy/weakness, and visual and auditory impairments comprise Leigh's syndrome. Despite these well-defined syndromes, their clinical expression often overlaps.

A number of factors make it difficult to assess whether a given treatment may be effective. These include:


  1. Mitochondrial cytopathies represent literally hundreds of different disease states. They may be caused by genetic mutations that result in deficient quantity or function of an enzyme, assembly of multisubunit enzymes, disorders of mitochondrial membrane structure, defects in substrate transport, or vitamin and cofactor deficiencies. The mutations themselves may involve nuclear DNA (nDNA) or mitochondrial DNA (mtDNA); point mutations, deletions, or rearrangements. It is not reasonable to believe that any one treatment would have a similar effect on all mitochondrial diseases.

  2. Mitochondrial diseases affect an unpredictable combination of a number of organs or organ systems. This is a result of the process known as segregative replication, in which the abnormal mitochondria may be "compartmentalized" within a given organ (i.e., muscle, brain) and not others. There may be a "threshold" effect in which a certain level of mutant mitochondrial genomes is required for disease to be evident clinically and/or biochemically.[1] Despite the existence of this critical threshold, the genetic burden or measured biochemical deficiency does not necessarily correlate with the severity or rapidity of progression of the disease. The variability of clinical features among affected family members is enormous, even if the underlying genetic or biochemical defect is the same. In addition, exacerbations and remissions are characteristic of these disorders, potentially clouding evaluation of the efficacy of a particular intervention.

  3. Mitochondrial diseases can be classified on the basis of a genetic defect, biochemical defect, or pathologic finding. Based on this classification, there are no defined methods of defining severity of illness, nor is there any understanding or consistent ability to predict the natural history of any one patient's illness. Therefore, treatment trials that are not conducted over a sufficient time period could reject a potentially adequate treatment.

  4. Given the potentially systemic nature of the mitochondrial cytopathies, developing a treatment trial looking at efficacy of a particular medication or supplement by evaluating the response of all possible affected organ systems would be quite cumbersome and expensive and would require an unacceptable number of patients. On the other hand, trials that look at the response of only one organ system to therapy may miss an existent benefit to other organ systems.

  5. The commonly investigated biochemical parameters (i.e., serum or cerebrospinal fluid lactate, pyruvate, enzyme assays) in isolation may not be a full indicator of therapeutic efficacy for any given supplement or medication. Monitoring progress via neurophysiologic studies, magnetic resonance spectroscopy (MRS), and/or objective muscle strength testing will likely add to the overall assessment of patients maintained on specific treatment regimens.


For these reasons, it is very unlikely that there will be class 1 proof that any specific medication or supplement will be effective in the treatment of mitochondrial cytopathies. There is good reason for this skepticism. At this time mitochondrial cytopathies are still considered by most to be relatively rare disorders. There are limited patients with any one specific mutation, and the clinical variability of those with a specific mutation is tremendous. Even if mitochondrial disorders are ultimately shown to be common, the vast phenotypic variability in terms of distribution of organ dysfunction and severity even among family members with identical genotypic disorders makes it impossible to know the natural history of disease progression (and unexplained occasional temporary remissions). Trying to collect class 1 data in a group of diseases with varied molecular genetics and biochemical defects is not likely to be possible.

Although there may be one best treatment approach for one individual with mitochondrial disease, it is naïve to think that there can be a unified treatment strategy for groups of patients identified as having a mitochondrial cytopathy. As mitochondrial diseases are often considered to be degenerative in nature, familiarity with the underlying pathophysiology of these disease processes can aid the clinician in developing potentially effective treatment regimens that can result in an improved quality of life. Despite this knowledge, therapy/amelioration of these disorders continues to pose quite a challenge. In general, therapeutic approaches are principally based on the use of antioxidants, vitamins and supplements ( Table 1. ), replacement of respiratory chain cofactors, dietary management, and medications aimed at reduction of a particular symptom (i.e., seizures, neuropathic pain, cardiac dysfunction).


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