Much research has linked mitochondrial dysfunction with aging and age-related syndromes such as Alzheimer’s disease (AD), but it remains unclear whether harm to these cellular powerhouses precedes or results from disease processes. Two new studies offer support for the former. From analysis of a series of mouse mutants, researchers in Sweden and Germany report in the August 21 Nature that mitochondrial DNA mutations present at birth can speed aging in animals with normal nuclear genomes. The finding raises the possibility that maternally inherited mitochondrial DNA variants could predispose to age-related disorders as well. Earlier, a research team in Spain reported in the June 22 Annals of Neurology that reduced mitochondrial DNA content in human spinal fluid serves as a marker for preclinical AD. The CSF changes showed up at least a decade before AD symptoms. While the studies differ, they both suggest mitochondrial changes as a driving force, rather than a consequence, of the aging process and AD pathogenesis.

Researchers led by Nils-Göran Larsson at the Max Planck Institute for Biology of Ageing, Cologne, Germany, and Lars Olson of the Karolinska Institute, Stockholm, Sweden, previously engineered mice with a proofreading-deficient mitochondrial polymerase, PolgA. They found that the animals racked up mitochondrial DNA (mtDNA) mutations faster than wild-type mice and aged prematurely (ARF related news story). In the current study, co-first authors Jaime Ross of the Karolinska and James Stewart of the Max Planck took the analysis one step further, asking whether premature aging could result from mtDNA mutations already present at birth.

PolgA mutant mice transmit mtDNA mutations through their germline (Ameur et al., 2011), making them suitable for studying the role of inherited mtDNA variants. Ross and colleagues crossed mice to generate lines with normal nuclear genomes (wt-N) but with or without inherited mtDNA mutations, as well as PolgA mutant mice with or without inherited mtDNA mutations.

Among wt-N mice, Larsson said, “if they inherited mtDNA mutations from their mother, they aged a bit more quickly.” PolgA mutant mice with inherited mtDNA mutations aged even faster, and displayed signs of premature aging, such as heart enlargement and reduced respiratory chain function. Furthermore, when Stewart and colleagues performed magnetic resonance imaging (MRI) on the brains of the mice to look for neuronal degeneration, they were surprised to find malformations in about a third of the PolgA mutant mice that inherited mtDNA mutations. The abnormalities included elongated hippocampi, striatal disturbances, and white matter changes, but no two mice looked the same. Brain malformations did not show up in mice with normal PolgA or without inherited mtDNA mutations. This suggests that “in order to get these malformations, (the mice) must inherit mtDNA mutations from their mother and have ongoing mutagenesis,” Larsson told Alzforum.

In the biomarker study, researchers led by Ramon Trullas of the Institute of Biomedical Research, Barcelona, Spain, took a different approach to ask whether mitochondrial changes precede the known biochemical signatures of AD. Based on their recent findings linking synaptic breakdown with mitochondrial transport (Clayton et al., 2012), first author Petar Podlesniy and colleagues wondered if release of mtDNA from damaged synapses into cerebrospinal fluid (CSF) could serve as a marker of neurodegeneration in AD. First, they verified they could use PCR to quantify free-floating mtDNA in human CSF—something not previously reported, they claim. The researchers measured mtDNA using real-time quantitative DNA amplification.

They then measured mtDNA in cell-free CSF samples from people with probable AD, asymptomatic at-risk individuals with low CSF Aβ1-42, age-matched healthy elderly, and, as an additional control, people with frontotemporal lobar degeneration (FTLD). Mitochondrial DNA content was substantially lower in probable AD and at-risk asymptomatic patients relative to the two control groups. The researchers were puzzled, but the findings held up in separate cohorts of sporadic AD cases and young presymptomatic patients with dominant presenilin 1 mutations. That CSF mtDNA levels were already low in presymptomatic patients suggested to the authors that mitochondrial dysfunction precedes symptom onset.

What might cause CSF mtDNA levels to drop in preclinical AD? At this point, Trullas has little insight into mechanisms. In light of a recent study reporting a 50 percent decrease in mtDNA copy number in postmortem AD brain (Coskun et al., 2010), he said their “best explanation is that this decrease in CSF mtDNA is an index of low mtDNA copy number in brain neurons.” Consistent with this idea, Podlesniy and colleagues measured the ratio of mtDNA to nuclear DNA in cultured cortical neurons from APP/PS1 transgenic mice and found they had 28 percent fewer mtDNA copies per cell compared to wild-type neurons.

“The two papers deal with different issues but ultimately circle back and tell a bigger story. They are both consistent with the mitochondrial cascade hypothesis,” said Russell Swerdlow of the University of Kansas Medical Center, Kansas City. This hypothesis holds that changes in mitochondrial function initiate the cascade that leads to AD, as opposed to beta-amyloid changes being upstream (see Swerdlow et al., 2010).

Bruce Yankner of Harvard Medical School, Boston, Massachusetts, said the mtDNA mutant mouse analyses were “elegantly done” and beg the question of whether inheritance of mtDNA mutations speeds aging in people as well. He suggested analyzing fibroblasts or lymphocytes from presymptomatic patients or people with AD risk factors (e.g. low CSF Aβ, apolipoprotein E4 allele) to see if they have more mtDNA mutations than usual.

In the biomarker study, Yanker said he would have liked to see analogous measurements in the APP/PS1 mice to determine if CSF mtDNA falls, and when, during the course of pathogenesis. If the human CSF findings can be replicated by other research groups, he thinks the assay is “worth pursuing because [a drop in CSF mtDNA] might be a useful very early biomarker, and may tell us something about the role of mitochondria in the pathogenesis of AD.” Flint Beal of Weill Cornell Medical College, New York, agreed. Beal added that the work opens up further questions—for example, how specific the reduction in CSF mtDNA is to AD, and how far in advance of symptom onset it occurs.—Esther Landhuis
References:
Ross JM, Stewart JB, Hagström E, Brené S, Mourier A, Coppotelli G, Freyer C, Lagouge M, Hoffer BJ, Olson L, Larsson NG. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature. 21 Aug 2013. Abstract

Podlesniy P, Silva- Figueiro J, Llado A, Antonell A, Sanchez-Valle R, Alcolea D, Lleo A, Molinuevo JL, Serra N, Trullas R. Low Cerebrospinal Fluid Concentration of Mitochondrial DNA in Preclinical Alzheimer Disease. Ann Neurol. 22 June 2013. Abstract

Comments

Make a Comment

To make a comment you must login or register.

Comments on News and Primary Papers

  1. This study advances the AD biomarker field by identifying a new marker, in this case cerebrospinal fluid (CSF) mitochondrial DNA (mtDNA) levels. The authors present data that suggest CSF mtDNA changes precede CSF Aβ changes. While one must use caution when considering the mechanistic implications of a biomarker change, or of potential mechanistic relationships between different biomarkers based solely on temporal relationships, the phenomenon reported in this paper suggests that mitochondrial changes may precede amyloid precursor protein (APP) processing or Aβ homeostasis changes in AD. In some ways this is not surprising, as APP processing and Aβ homeostasis are exquisitely regulated processes, and bioenergetic function is one factor that is known to influence both.

    View all comments by Russell Swerdlow
  2. Small changes in the mitochondrial DNA (mtDNA) can lead to severe effects over time. Recently, we have shown that minor base changes in the mtDNA of conplastic mouse strains in the C57Bl/6 genomic background may affect hallmarks of AD (Scheffler et al., 2012). Alterations in ATP-production caused by mtDNA changes resulted in direct suppression of beta-amyloid clearance from the brain by ATP-depending exporters (ABC transporters). Microglial function was also compromised.

    Researchers continue to debate the role maternal inheritance in the pathogenesis of sporadic AD. Consistently, even small mitochondrial genomic abberations may show long-term effects that converge in aging and neurodegeneration.

    References:

    . Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis. Acta Neuropathol. 2012 Aug;124(2):199-208. PubMed.

  3. These are exciting findings that make important contributions to an ever growing body of science indicating that perturbation in mitochondrial function is an early and antecedent event in the pathogenesis of neurodegenerative diseases such as Alzheimer’s. These latest findings are consistent with our previous report that mitochondrial / bioenergetic deficits precede appearance of AD pathology in female mouse models of Alzheimer’s disease. It was surprising to us that the bioenergetic deficit was evident even in embryonic neurons derived from the same mouse model (Yao et al., 2009). Analyses in humans by Mosconi and Swerdlow are consistent with these preclinical studies where they found reduced mitochondrial cytochrome c oxidase activity in platelets and reduced brain glucose metabolism in adult children with maternal history of Alzheimer’s disease (Mostoni et al., 2010; Mosconi et al., 2011).

    <p>Collectively a growing body of data from preclinical to clinical indicate that deficits in mitochondrial function are likely a risk factor for late-onset Alzheimer’s disease. These findings also indicate the therapeutic potential of targeting mitochondria for disease prevention.

    References:

    . Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14670-5. PubMed.

    . Maternal transmission of Alzheimer's disease: prodromal metabolic phenotype and the search for genes. Hum Genomics. 2010 Feb;4(3):170-93. PubMed.

    . Reduced mitochondria cytochrome oxidase activity in adult children of mothers with Alzheimer's disease. J Alzheimers Dis. 2011;27(3):483-90. PubMed.

References

News Citations

  1. Poor Proofreading May Shorten Your Lifespan

Paper Citations

  1. . Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. PLoS Genet. 2011 Mar;7(3):e1002028. PubMed.
  2. . NP1 regulates neuronal activity-dependent accumulation of BAX in mitochondria and mitochondrial dynamics. J Neurosci. 2012 Jan 25;32(4):1453-66. PubMed.
  3. . Systemic mitochondrial dysfunction and the etiology of Alzheimer's disease and down syndrome dementia. J Alzheimers Dis. 2010;20 Suppl 2:S293-310. PubMed.
  4. . The Alzheimer's disease mitochondrial cascade hypothesis. J Alzheimers Dis. 2010;20 Suppl 2:S265-79. PubMed.
  5. . Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature. 2013 Sep 19;501(7467):412-5. PubMed.
  6. . Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease. Ann Neurol. 2013 Jun 22; PubMed.

Further Reading

Papers

  1. . Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease. Ann Neurol. 2013 Jun 22; PubMed.
  2. . Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004 May 27;429(6990):417-23. PubMed.

Primary Papers

  1. . Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature. 2013 Sep 19;501(7467):412-5. PubMed.
  2. . Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease. Ann Neurol. 2013 Jun 22; PubMed.