Mitochondrial Encephalomyopathiesq

S DiMauro, K Tanji, and EA Schon, Columbia University Medical Center, New York, NY, United States
Ó 2017 Elsevier Inc. All rights reserved.

Introduction 1
Respiratory Chain 2
Human Mitochondrial DNA 3
Heteroplasmy and Threshold Effect 3
Mitotic Segregation 4
Maternal Inheritance 4
Disorders due to Defects of mtDNA 4
mtDNA Rearrangements 4
Point Mutations 5
mtDNA Mutation Effects 6
Disorders due to Defects of Nuclear DNA 6
Mutations in Genes Encoding Subunits of the Respiratory Chain 6
Mutations in Genes Encoding Ancillary Respiratory Chain Proteins 6
Defects of Intergenomic Signaling (of mtDNA Maintenance) 6
Defects of mtDNA Translation 7
Defects of Phospholipid Composition of Mitochondrial Membranes 7
Defects of Mitochondria in Neurodegenerative Diseases 7
Defects in Mitochondrial Dynamics 8
Further Reading 8

Introduction

Mitochondrial myopathies were described in the early 1960s, when systematic ultrastructural and histochemical studies revealed
excessive proliferation of normal–or abnormal-looking mitochondria in muscle of patients with weakness or exercise intolerance.
Because the areas of mitochondrial accumulation looked purplish with the modified Gomori trichrome stain (Fig. 1A), the
abnormal fibers were dubbed ragged-red (RRFs). When systematic ultrastructural and histochemical studies revealed RRFs in muscle
of patients associated with symptoms and signs of brain involvement, the term “mitochondrial encephalomyopathies” was intro-
duced. It also became clear that lack of RRFs in the biopsy does not exclude a mitochondrial etiology, as exemplified by Leigh
syndrome (LS), an encephalopathy of infancy or childhood invariably due to mitochondrial dysfunction but rarely accompanied
by RRFs. More recently, a further improvement in diagnostic histochemistry has been developed, consisting of the superimposed
staining of succinate dehydrogenase (SDH) activity (in blue) and of cytochrome c oxidase (COX) activity (in brown). In normal

Figure 1 Illustration of ragged-red fibers (RRFs) revealed by the modified Gomori trichrome stain, showing abnormal accumulations of mitochon-
dria as reddish blotches, mostly at the periphery of muscle fibers (A). In (B), a serial cross-section from the muscle biopsy shows ragged-blue fibers,
highlighted by the histochemical stain for succinate dehydrogenase (SDH), that are not obscured by the COX-positive fibers (brown).

q
Change History: April 2016. S DiMauro, K Tanji, and EA Schon updated the text to the article and modified Figures 1, 3, and 4.

Reference Module in Neuroscience and Biobehavioral Psychology http://dx.doi.org/10.1016/B978-0-12-809324-5.01974-X 1

2 Mitochondrial Encephalomyopathies

muscle fibers, the brown stain prevails, but occasional pathological fibers will appear blue (“ragged-blue fibers”) but not brown
(i.e., showing increased mitochondrial number but decreased COX activity). This refined technique will reveal ragged-blue/
COX-deficient fibers better than RRFs (Fig. 1B).
According to the widely accepted “endosymbiotic hypothesis,” mitochondria are the remnants of proteobacteria that populated
anaerobic nucleated cells and endowed them with the precious gift of oxidative metabolism. Thus, mitochondria are the main
source of energy for all human tissues and contain many metabolic pathways some of which [e.g., the pyruvate dehydrogenase
complex (PDHC), the carnitine cycle, the b-oxidation “spirals,” the tricarboxylic acid (TCA) cycle], and the CoQ10 biosynthetic
pathway, are shown in Fig. 2.

Respiratory Chain

Although defects in all of the aforementioned metabolic pathways are by definition mitochondrial diseases, the term “mitochon-
drial encephalomyopathy” has come to indicate disorders due to defects in the respiratory chain. This is the “business end” of oxida-
tive metabolism, where adenosine triphosphate (ATP) is generated. Reducing equivalents produced in the TCA cycle (also known as
the Krebs cycle) and in the b-oxidation spirals are passed along a series of protein complexes embedded in the inner mitochondrial
membrane (the electron transport chain). The electron transport chain consists of four multimeric complexes (I to IV) plus two
small electron carriers, coenzyme Q10 (or ubiquinone) and cytochrome c. The energy generated by these reactions is used to
pump protons from the mitochondrial matrix into the space between the inner and outer mitochondrial membranes. This creates
an electrochemical proton gradient, which is utilized by complex V (or ATP synthase) to produce ATP in a process known as oxida-
tive phosphorylation.
A unique feature of the respiratory chain (Fig. 2) is its control by two distinct genomes, the nuclear DNA (nDNA) and the mito-
chondrial DNA (mtDNA). Of the approximately 80 proteins that make up the respiratory chain, 13 are encoded by mtDNA and all
the others are encoded by nDNA. Complex II, coenzyme Q10, and cytochrome c are encoded exclusively by nDNA. In contrast,
complexes I, III, IV, and V contain some subunits encoded by mtDNA: seven for complex I, one for complex III, three for complex
IV, and two for complex V (see also Fig. 4).

Figure 2 Schematic representation of mitochondrial metabolism. ADP, adenosine diphosphate; ANT, adenine nucleotide translocator; ATP, adenosine
triphosphate; CPT, carnitine palmitoyltransferase; CoA, coenzyme A; DIC, dicarboxylate carrier; TCA, tricarboxylic acid; ETF, electron transfer flavopro-
tein; FADH2, flavin adenine dinucleotide, reduced form; NADH, nicotinamide adenine dinucleotide, reduced form; I, II, III, IV, V, complexes of the respi-
ratory chain; CoQ, coenzyme Q and its biosynthetic pathway; Cyt c, cytochrome c; PDHC, pyruvate dehydrogenase complex.
 Mitochondrial Encephalomyopathies 3

Human Mitochondrial DNA

Human mtDNA (Fig. 3) is a 16 569-bp circular, double-stranded molecule, which contains 37 genes: 2 rRNA genes, 22 tRNA genes,
and 13 structural genes encoding the aforementioned respiratory chain subunits. In the course of evolution, mtDNA has lost much
of its original autonomy and now depends heavily on the nuclear genome for the production of factors needed for mtDNA tran-
scription, translation, and replication. Since 1988 (when mutations in mtDNA were first associated with human disease), the circle
of mtDNA has become crowded with pathogenic mutations, and the principles of mitochondrial genetics should, therefore, be
familiar to the practicing physician.

Heteroplasmy and Threshold Effect

Each cell contains hundreds or thousands of mtDNA copies, which, at cell division, distribute randomly among daughter cells. In
normal tissues, all mtDNA molecules are identical (homoplasmy). Deleterious mutations in mtDNA that coexist with normal

Figure 3 Morbidity map of the human mitochondrial genome as of 2015. The map of the 16 569-bp mitochondrial genome shows different colored
areas representing the protein-coding genes for the seven subunits of complex I (NADH dehydrogenase, ND, in pink), the three subunits of cyto-
chrome c oxidase (COX, in purple), cytochrome b (Cyt b, in light blue), and the two subunits of ATP synthetase (A8/6, in yellow), the 12S and 16S
ribosomal RNAs (12S, 16S, in green), and the 22 transfer RNAs (tRNA, in dark blue), identified by one-letter codes for the corresponding amino
acids. Number of mutations in each gene (red, protein coding; blue, protein synthesis) are circled, with typical/common disease entities associated
with each. FBSN, familial bilateral striatal necrosis; KSS, Kearns–Sayre syndrome; LHON, Leber hereditary optic neuropathy; MELAS, mitochondrial
encephalomyopathy, lactic acidosis, and strokelike episodes; MERRF, myoclonic epilepsy with ragged-red fibers; MILS, maternally inherited Leigh
syndrome; NARP, neuropathy, ataxia, retinitis pigmentosa; PEO, progressive external ophthalmoplegia.
4 Mitochondrial Encephalomyopathies

mtDNAs (heteroplasmy) usually affect some but not all mtDNAs within a cell, a tissue, and an individual. The clinical expression of
a pathogenic mtDNA mutation is largely determined by the relative proportion of normal and mutant genomes in different tissues.
A minimum critical number of mutant mtDNAs is required to cause mitochondrial dysfunction in a particular organ or tissue, and
mitochondrial disease in an individual (threshold effect).

Mitotic Segregation

At cell division, the proportion of mutant mtDNAs in daughter cells may shift and the phenotype may change accordingly. This
phenomenon, called mitotic segregation, explains how certain patients with mtDNA-related disorders may actually shift from
one clinical phenotype to another as they grow older.

Maternal Inheritance

At fertilization, all mtDNA derives from the oocyte. Therefore, the mode of transmission of mtDNA and of most mtDNA point
mutations (single deletions of mtDNA are usually sporadic events) differs from that of Mendelian inheritance. A mother carrying
a mtDNA point mutation will pass it on to all of her children (males as well as females), but only her daughters will transmit it to
their progeny. A disease expressed in both sexes but with no evidence of paternal transmission is strongly suggestive of an mtDNA
point mutation. The best way for the clinician to chart a course toward a diagnosis in the jungle of mitochondrial encephalomyo-
pathies is to use a classification that combines genetic and biochemical criteria (Table 1). From the genetic point of view, there are
two major categories, disorders due to defects of mtDNA and disorders due to defects of nDNA (Fig. 4).

Disorders due to Defects of mtDNA

Disorders due to defects of mtDNA include rearrangements (single partial deletions or duplications) and point mutations.

mtDNA Rearrangements

Single partial deletions of mtDNA have been associated with three sporadic conditions:
1. Pearson syndrome, a usually fatal disorder of infancy characterized by sideroblastic anemia and exocrine pancreas dysfunction.
2. Kearns-Sayre syndrome (KSS), a usually fatal disorder with onset before age 20, characterized by impaired eye movements
(progressive external ophthalmoplegia; PEO), pigmentary retinopathy, and heart block. Frequent additional signs
include ataxia, dementia, and endocrine problems (diabetes mellitus, short stature, hypoparathyroidism). Lactic acidosis,
elevated cerebrospinal fluid (CSF) protein (over 100 mg dL
1), and RRFs in the muscle biopsy are typical laboratory
abnormalities.
3. PEO with or without proximal limb weakness, often compatible with a normal life span. In all three disorders the deletions vary
in size and location, but a “common” deletion of 5 kb is frequently seen in patients and in aged individuals (Fig. 3).
Duplications of mtDNA can occur in isolation or together with single deletions and have been seen in patients with KSS or with
diabetes mellitus and deafness. Duplications and duplications/deletions (as well as the associated phenotypes) are transmitted by
maternal inheritance.

Table 1 Genetic classification of mitochondrial encephalomyopathies

Mitochondrial DNA (mtDNA)-related diseases (maternal or sporadic)

1. Single deletions (sporadic)
2. Point mutations (maternally inherited)
Nuclear DNA (nDNA)-related diseases (mendelian)
1. “Direct hits”
2. “Indirect hits”
3. Defects of mtDNA maintenance (mtDNA depletion and multiple
deletions)
4. Defects of mtDNA translation
5. Defects of the inner mitochondrial membrane lipid milieu
6. Defects of mitochondrial dynamics
 Mitochondrial Encephalomyopathies 5

Figure 4 Schematic representation of the mitochondrial respiratory chain, showing nDNA-encoded (blue) and mtDNA-encoded (red) subunits.
Electrons (e
) flow along the electron-transport chain, and protons (Hþ) are pumped, first from the matrix into the intermembrane space through
complexes I, III, and IV, then back into the matrix through complex V to generate ATP. Disorders due to mutations in mtDNA are listed above, and
those in nuclear genes are listed below, the defective respiratory chain complexes. Gene products in bold are structural components of the OxPhos
system; those in plaintext are ancillary proteins (see text). GRACILE, growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and
early death. Other notation as in Fig. 3.

Point Mutations

Almost 300 pathogenic point mutations have been identified in mtDNA from patients with a variety of disorders, most of which are
maternally inherited and multisystemic, but some of which are sporadic and tissue specific (Fig. 3). Among the maternally inherited
encephalomyopathies, four syndromes are more common. The first is MELAS (mitochondrial encephalomyopathy, lactic acidosis,
and strokelike episodes), which usually presents in children or young adults after normal early development. Symptoms include
recurrent vomiting, migraine-like headache, and strokelike episodes causing cortical blindness, hemiparesis, or hemianopia.
Magnetic resonance imaging (MRI) of the brain shows “infarcts” that do not correspond to the distribution of major vessels, raising
the question of whether the strokes are vascular or metabolic in nature. The most common mtDNA mutation is A3243G in the
tRNALeu(UUR) (MT-TL1) gene, but about a dozen other mutations have been associated with MELAS, most notably a mutation
(G13513A) in the MT-ND5 gene, which encodes subunit 5 of complex I.
The second syndrome is MERRF (myoclonus epilepsy with ragged red fibers), characterized by myoclonus, seizures, mitochon-
drial myopathy, and cerebellar ataxia. Less common signs include dementia, hearing loss, peripheral neuropathy, and multiple
lipomas. Three mtDNA mutations (A8344G, T8356C, and G8363A) have been associated with MERRF and all are in the tRNALys
(MT-TK) gene.
The third syndrome comes in two forms: (1) NARP (neuropathy, ataxia, retinitis pigmentosa) usually affects young adults and
causes retinitis pigmentosa, dementia, seizures, ataxia, proximal weakness, and sensory neuropathy; (2) maternally inherited Leigh
syndrome (MILS) is a more severe infantile encephalopathy with characteristic symmetrical lesions in the basal ganglia and the
brain stem. Both are associated with mutations at position 8993 in MT-ATP6.
6 Mitochondrial Encephalomyopathies

The fourth syndrome, LHON (Leber hereditary optic neuropathy), is characterized by acute or subacute loss of vision in young
adults, more frequently males, due to bilateral optic atrophy. Three mtDNA point mutations in NADH dehydrogenase (ND) genes
(encoding subunits of complex I) have been associated with LHON. These are G11778A in MT-ND4, G3460A in MT-ND1, and
T14484C in MT-ND6.

mtDNA Mutation Effects

Not surprisingly, syndromes associated with mtDNA mutations can affect every system in the body, including the visual (optic
atrophy, retinitis pigmentosa, cataracts), auditory (neurosensory deafness), and endocrine (short stature, diabetes mellitus, hypo-
parathyroidism) systems, the heart (familial cardiomyopathies, conduction blocks), the gastrointestinal tract (exocrine pancreas
dysfunction, intestinal pseudoobstruction, gastroesophageal reflux), and the kidney (renal tubular acidosis or glomerular
nephrosis). Any combination of the aforementioned symptoms and signs should raise the suspicion of a mitochondrial disorder,
especially if there is evidence of maternal transmission. On the other hand, point mutations in mtDNA protein-coding genes often
escape the rules of mitochondrial genetics in that they can affect single individuals and single tissues, most commonly skeletal
muscle. Thus, patients with exercise intolerance, myalgia, and, sometimes, recurrent myoglobinuria, may have isolated defects of
complex I, complex III, or complex IV, due to pathogenic mutations in genes encoding ND subunits, cytochrome b, or cytochrome
c oxidase (COX) subunits. The lack of maternal inheritance and the involvement of muscle alone suggest that mutations can arise de
novo in myogenic stem cells after germ-layer differentiation (“somatic mutations”).

Disorders due to Defects of Nuclear DNA

Disorders due to defects of nDNA are all transmitted by Mendelian inheritance and include six major subgroups.

Mutations in Genes Encoding Subunits of the Respiratory Chain

As noted above, mtDNA encodes only 13 subunits of the respiratory chain, while nDNA encodes all the subunits of complex II and
most of the subunits of the other four complexes, as well as coenzyme Q10 (CoQ10) and cytochrome c. Nuclear DNA mutations can
affect respiratory chain complexes directly or indirectly. Direct “hits”dthat is, mutations in genes encoding respiratory chain sub-
unitsdare known mostly for complex I and complex II. These have been associated with autosomal recessive forms of Leigh
syndrome (Fig. 4).

Mutations in Genes Encoding Ancillary Respiratory Chain Proteins

Indirect “hits” are mutations in genes encoding proteins that are not components of the respiratory chain, but are needed for proper
assembly and function of respiratory chain complexes. This “murder by proxy” mechanism has been identified in disorders due to
defects in complexes I, III, IV, and V, but is best illustrated by Mendelian defects of complex IV (cytochrome c oxidase). Mutations in
six ancillary proteins (SURF1, SCO2, SCO1, COX10, COX15, and LRPPRC) have been associated with COX-deficient Leigh
syndrome or other multisystemic fatal infantile disorders in which encephalopathy is accompanied by cardiomyopathy (SCO2,
COX15), nephropathy (COX10), or hepatopathy (SCO1).
Primary or secondary CoQ10 deficiency can cause four major syndromes: (1) a predominantly myopathic disorder with recurrent
myoglobinuria but also central nervous system involvement (seizures, ataxia, mental retardation), (2) a predominantly encepha-
lopathic disorder with ataxia and cerebellar atrophy, (3) an isolated myopathy, with RRFs and lipid storage, and (4) a generalized
mitochondrial encephalomyopathy, usually with onset in infancy. An example of secondary CoQ10 deficiency is that associated
with mutations in aprataxin (APTX), which cause ataxia oculomotor apraxia type 1 (AOA1). Examples of primary CoQ10 deficiency
include mutations in 6 of the 10 confirmed human CoQ biosynthetic genes, ADCK3, COQ2, COQ4, COQ9, PDSS1, and PDSS2.
Irrespective of etiology, diagnosis is important because most patients with CoQ10 deficiency respond to high-dose CoQ10
supplementation.
This is a burgeoning field of research with important theoretical and practical implications. From an investigative point of view,
these disorders teach us a lot about the structural and functional complexity of the respiratory chain. At a more practical level, iden-
tification of mutations in the related genes renders prenatal diagnosis available and suggests approaches to therapy, such as copper
administration to infants with mutations in SCO2, a copper-carrying protein.

Defects of Intergenomic Signaling (of mtDNA Maintenance)

As noted previously, mtDNA is highly dependent for its proper function and replication on numerous factors encoded by nuclear
genes. Mutations in these genes cause Mendelian disorders characterized by qualitative or quantitative alterations of mtDNA.
 Mitochondrial Encephalomyopathies 7

Examples of qualitative alterations include autosomal dominant or autosomal recessive multiple deletions of mtDNA, usually
accompanied clinically by PEO plus a variety of other symptoms and signs. Mutations in the gene for one isoform of the adenine
nucleotide translocator (ANT1) have been identified in some patients with autosomal dominant PEO. Mutations in the PEO1 gene,
encoding Twinkle, a helicase, are also associated with autosomal dominant PEO, whereas mutations in the gene encoding poly-
merase gamma (POLG) may cause either autosomal dominant or autosomal recessive PEO. Interestingly, all of these mutations
affect genes involved in the homeostasis of the mitochondrial nucleotide pool and probably have similar pathogenic mechanisms.
Examples of quantitative alterations of mtDNA include severe or partial mtDNA depletion, usually characterized clinically by
congenital or childhood forms of autosomal recessively inherited myopathy or hepatopathy. Mutations in five genes, four of
them involved in mitochondrial nucleotide homeostasis, have been associated with mtDNA depletion syndromes, although
they still do not explain all cases. Mutations in the gene encoding thymidine kinase 2 (TK2) are often seen in patients with
myopathic mtDNA depletion syndromes, whereas mutations in the gene (SUCLA2), encoding the b subunit of the mitochondrial
matrix enzyme succinyl-CoA synthetase, cause both myopathy and encephalopathy. Mutations in DGUOK, encoding deoxyguano-
sine kinase, predominate in patients with hepatic or hepatocerebral mtDNA depletion syndromes, but, as mentioned previously,
mutations in POLG are the major causes of Alpers syndrome, predominating in patients with hepatic or hepatocerebral mtDNA
depletion syndromes. Mutations in MPV17) not involved in nucleotide pool homeostasis have been associated with hepatocerebral
syndrome and with the Navajo neurohepatopathy (NNH) syndrome, prevalent in the Navajo population of Southwestern Unites
States.
Examples of “mixed” qualitative and quantitative mtDNA alterations have been characterized at the molecular level. Mutations
in the gene for thymidine phosphorylase (TYMP) are responsible for an autosomal recessive multisystemic syndrome called MNGIE
(mitochondrial neurogastrointestinal encephalomyopathy). Autosomal recessive mutations in POLG also cause an mtDNA deple-
tion syndrome involving liver and brain, known as Alpers or Alpers syndrome (see above).

Defects of mtDNA Translation

A new group of defects is due to mutations in genes encoding factors necessary for the faithful translation of mtDNA-encoded
proteins, including EFG1 (encoding elongation factor 1), TSFM and TUFM (encoding elongation factors Ts and Tu), and
C12orf65 (encoding a translation release factor). The resulting disorders usually affect infants and cause severe
encephalomyopathy, cardiomyopathy, and sideroblastic anemia. In addition, recessive mutations have been identified in at least
6 tRNA modification enzymes, 7 mitoribosomal proteins, and 15 mitochondrially-localized aminoacyl-tRNA synthetases.
Typically, both quality and quantity of mtDNA are normal in these patients, but there arednot surprisinglydmultiple
respiratory chain defects involving all complexes containing mtDNA-encoded subunits.

Defects of Phospholipid Composition of Mitochondrial Membranes

The lipid milieu of the inner mitochondrial membrane (IMM) is not just a scaffold holding the respiratory chain but is an integral
component of its function. Barth syndrome, an X-linked myopathy, cardiomyopathy, and leukopenia, is due to mutations in the
tafazzin (TAZ) gene, causing deficiency or abnormal composition of cardiolipin, the major phospholipid component of the IMM. A
similar disorder, with myopathy, cardiomyopathy, and congenital cataract (Sengers syndrome) is due to mutations in the AGK gene
encoding acylglycerol kinase, which phosphorylates intermediates in the synthesis of phospholipids. A form of human congenital
muscular dystrophy, with giant mitochondria displaced to the periphery of fibers, is due to mutations in the gene encoding choline
kinase beta (CHKB). A syndrome characterized by 3-methylglutaconic aciduria type IV, deafness, and Leigh-like encephalopathy
(dubbed MEGDEL) is attributed to mutations in the gene serine active site containing 1 (SERAC1), which is essential for
mitochondrial function and cholesterol trafficking.
Great interest has recently arisen in mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), a lipid raft-like
subdomain of the ER that is apposed to, and communicates with, mitochondria. MAM is involved in phospholipid and cholesterol
homeostasis, calcium signaling, and mitochondrial dynamics. Pathogenic alterations in MAMs have been established in causing
above syndromes, such as MEGDEL due to mutations in SERAC1, and probably to congenital muscular dystrophy due to CHKB
mutations as well. Moreover, some forms of primary lateral sclerosis or juvenile amyotrophic lateral sclerosis (ALS) are due to muta-
tions in ERLIN2, a MAM-localized protein that affect lipid raft formation.

Defects of Mitochondria in Neurodegenerative Diseases

Late-onset neurodegenerative diseases are typically characterized by the selective death of neuronal subtypes. Phenotypically, there
are disturbances in cellular quality control mechanisms, oxidative stress, and impaired subcellular trafficking. Increasingly, impaired
mitochondrial function has also been recognized as a key aspect of these disorders, not only regarding energy production but also
mitochondrial dynamics (i.e., organellar fission, fusion, shape, size, distribution, anchorage, and movement) and communication
8 Mitochondrial Encephalomyopathies

with other organelles. Only in the last few years has this latter category been recognized as a prominent aspect of neurodegenerative
disorders.

Defects in Mitochondrial Dynamics

Mitochondria are dynamic organelles, engaged in repeated cycles of fusion and fission and actively recruited to subcellular sites,
such as axonal and dendritic processes of neurons. Additionally, quality control of mitochondria is established through mitophagy,
a form of autophagy selectively degrading defective mitochondria.
Among disease associated with defects in mitochondrial dynamics, oneddominant optic atrophy (DOA), caused by mutations
in OPA1dis the mendelian counterpart of maternally-inherited Leber hereditary optic neuropathy (LHON). OPA1 is a dynamin-
related GTPase located in the IMM that, together with mitofusin-1 (MFN1), another GTPase located on the OMM, promotes mito-
chondrial fusion. Conversely, mutations in two mitochondrial fission proteins, DRP1 (dynamin-related protein 1; gene DNM1L)
and MFF (mitochondrial fission factor) cause fatal infantile neurological disorders, with microcephaly, optic atrophy, truncal hypo-
tonia, and lactic acidosis. Mutations in another fission-related protein, ganglioside-induced differentiation-associated protein
(GDAP1), causes Charcot-Marie-Tooth disease type 4A (CMT4A), a peripheral neuropathy. Diseases associated with defects in mito-
chondrial trafficking include those due to mutations in spastin (SPAST), a microtubule severing protein, causing hereditary spastic
paraplegia type 4, and in neurofilament light chain (NEFL), causing CMT2E.
Diseases associated with defects in mitochondrial quality control include familial Parkinson disease associated with mutations
in PINK1 (PTEN-induced putative kinase 1), a kinase, and parkin (PARK2), an E3 ubiquitin ligase associated with protein
degradation via the proteasome: both proteins appear to operate together to remove dysfunctional mitochondria via mitophagy.
Finally, there are diseases associated with defects in the communication between mitochondria and other organelles, especially
the endoplasmic reticulum (ER), at mitochondria-associated ER membranes, or MAM. Interestingly, mitofusin-2 (MFN2),
a homolog of MFN1, regulates the apposition between ER and mitochondria; when mutated it causes another peripheral neurop-
athy CMT2A. While MFN2 promotes ER-mitochondrial connectivity, presenilin-1 (PSEN1) and presenilin-2 (PSEN2), which are
associated with Alzheimer disease, act in the opposite way, perhaps helping explain some of the mitochondrial deficits found in
that disorder.

Further Reading

DiMauro, S., 2013. Mitochondrial encephalomyopathies: fifty years on. Neurology 81, 281–291.
DiMauro, S., Schon, E.A., Hirano, M., Carelli, V., 2013. The clinical maze of mitochondrial neurology. Nat. Rev. Neurol. 9, 429–444.
Engelstad, K., Sklerov, M., Kriger, J., et al., 2016. Attitudes toward prevention of mtDNA-related diseases through oocyte mitochondrial replacement therapy. Hum. Reprod. 31,
1058–1065.
Pearce, S., Nezich, C.L., Spinazzola, A., 2013. Mitochondrial diseases: translation matters. Mol. Cell. Neurosci. 55, 1–12.
Pfeffer, G., Horvath, R., Klopstock, T., et al., 2013. New treatments for mitochondrial diseases – no time to drop our standards. Nat. Rev. Neurol. 9, 474–481.
Schon, E.A., DiMauro, S., Hirano, M., 2012. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat. Rev. Genet. 13, 878–890.
Schon, E.A., Przedboski, S., 2011. Mitochondria: the next (neuro)degeneration. Neuron 70, 1033–1053.