Mitochondria, cholesterol and pH

‘or why dietary cholesterol is good for you and might keep you sane’

It is well known that bacterial (and fungal growth) is inhibited by low pH conditions. Mankind has made use of this for thousands of years by pickling food in vinegar in order to preserve it. Mitochondria inside aging yeast cells have been shown to be inhibited in activity and number from a decrease in the pH of their environment. This was attributed to leakage of acid from cell vacuoles (similar in function to mammalian lysosomes1). This is not surprising given that mitochondria and bacteria use similar chemiosmotic methods to produce sufficient energy to grow and divide.

In my Ph.D thesis I similarly found leaking, fragile lysosomes in the livers of aged rats2  which I attributed to the age-related lower levels of cholesterol I found in their membranes; it was well known that cholesterol stabilised lysosomal membranes3.  A lowering of cellular pH as a result of acid leaking from lysosomes, or alternatively if not actually lowering the pH a ‘using up’ of the buffering capacity of the cytoplasm, would affect mitochondria. This is because they depend on their proton-pumps to generate the electrochemical gradient they use to generate chemical energy in the form of ATP. In turn, a proton-pump can be called an acid-pump... and it only gets harder to make the pH gradient needed if the environment of the mitochondria is becoming acidified.

Another piece of research work, again in yeast, showed that simvastatin adversely affected mitochondrial function3. My work has shown that mitochondria conserve ( hang-on-to and regulate) the cholesterol in their inner mitochondrial membrane until no cholesterol is available to do so but the other membranes in the cell do not. It is speculation, but I wonder if low levels of membrane cholesterol contribute to mitochondrial dysfunction with age …  as a result of leaking acid from fragile lysosomes.

Feeding aged rats cholesterol.

I conducted a series of experiments feeding cholesterol to young and old rats4. It raised the intracellular levels of cholesterol and the amount of cholesterol in the membranes of lysosomes and the outer mitochondrial membrane as expected, but did not affect the inner mitochondrial membrane in either age group. The function of mitochondria was also unaffected in either group, old mitochondria. What was interesting, and completely unremarked upon at the time, was the effect on Cytochrome C release. Old mitochondria more easily lose Cytochrome C and this is now known to be the trigger for the initiation of cell death in senescence (apoptosis). Cholesterol feeding reversed this change. Its significance was lost to me then but now seems important. I speculated then that the increased cholesterol content of the outer mitochondrial membrane was containing the Cytochrome C. The lysosmes also contained more cholesterol but I did no experiments on their fragility or leakiness.

I have long been of the opinion that cholesterol plays a pivotal role in the ageing process. I have gone as far as to write a recipe book giving my top cholesterol rich meals. It is published online here5. I am not of the persuasion that dietary cholesterol is bad for you, entirely the opposite. My book shows how those on high cholesterol diets have traditionally fared well in terms longevity, physical and mental health. I watch avidly for confirmation in all sorts of published work. My two current favorites are: ‘the obese suffer less from dementia as they age6’ and ‘those who lose weight during the middle decades suffer more7’. I see the bio-print of cholesterol in both.

Without realising it I already had some pointer that cholesterol may inhibit the ageing process by stabilising membranes. And thereby potentially reducing acid leakage from lysosomes and definitely reducing deadly Cytochrome C leaks from mitochondria.

This post started with the problem of intra-cellular acidity and ended with cholesterol. Mitochondria remain for me the key to the ageing process, the puzzle is unlocking the processes behind their induced senescence. I say ‘induced’ because in a previous post I have pointed out that when an old cell divides the mitochondria replicate and are rejuvenated8. The role that cholesterol plays in keeping the story together remains as yet untold.

My investigations into high cholesterol diets being associated with longevity and mental/physical health in ‘Food for the Over Fifties5’ was based on correlation. In other words it has the same status scientifically as the much loved ‘risk factors’ of the medical profession. However the result that high membrane cholesterol ( as a result of a high cholesterol diet) prevents the release of the major apotoptic factor Cytochrome is in the domain of ‘causal’. Maybe dietary cholesterol  really is good for you especially if you are old and worried about losing brain cells to apoptosis?

References:

1)

Nature. Author manuscript; available in PMC 2013 Jun 13. Published in final edited form as:
Nature. 2012 Dec 13; 492(7428): 261–265. Published online 2012 Nov 21. doi:  10.1038/nature11654
PMCID: PMC3521838 NIHMSID: NIHMS412617
An Early-Age Increase in Vacuolar pH Limits Mitochondrial Function andLifespan in Yeast
Adam L. Hughes1 and Daniel E. Gottschling1

2) The Cholesterol Content of Mitochondria from Mature and Old Rats P 205

Age-related changes in Rat Liver Mitochondria J A Spencer Ph.D thesis 1980 Birmingham University, unpublished work.

3)

Simvastatin reduces ergosterol levels, inhibits growth and causes loss of mtDNA inCandida  glabrata Christine Westermeyer & Ian G. Macreadie CSIRO

Health and Molecular and Technologies and P-Health Flagship, Parkville, Victoria, Australia

4)      The Cholesterol Content of Mitochondria from Mature and Old Rats P151-160

Age-related changes in Rat Liver Mitochondria J A Spencer Ph.D thesis 1980 Birmingham University, unpublished work.

5) Food for the over fifties: http://pub.lucidpress.com/d7eeae2f-fdca-4d5f-ac0a-bd534a0a958c/

6) The Lancet: Diabetes and Endocrinology, Volume 3, No. 6, p431–436, June 2015

BMI and risk of dementia in two million people over two decades: a retrospective cohort study Dr Nawab Qizilbash, MRCPJohn Gregson, PhD Michelle E Johnson, MSc Prof Neil Pearce, PhD Ian Douglas, PhD Kevin Wing, MSc Prof Stephen J W Evans, MSc Prof Stuart J Pocock, PhD

7)

ARCH NEUROL / VOL 62, JAN 2005 WWW.ARCHNEUROL.COM 55 A 32-Year Prospective Study of Change in Body Weight and Incident Dementia The Honolulu-Asia Aging Study Robert Stewart, MD; Kam

8)

REVERSAL OF AGE-DEPENDENT DECLINE IN RESPIRATORY CONTROL RATIO BY HEPATIC REGENERATION HORTON, AA; SPENCER, JA  FEBS LETTERS  Volume: 133   Issue: 1   Pages: 139-141   DOI: 10.1016/0014-5793(81)80490-5   Published: 1981 Times Cited: 4 (from Web of Science)