A mitochondrially mediated mechanism for cellular senescence

 

A mitochondrially mediated mechanism for cellular senescence and apoptosis.

Fifty years ago in my PhD thesis on the aging  of rat liver mitochondria I described and produced electron micrographs of a population of mega-mitochondria within the liver cells of senescent rats. This population was also evident when isolated from ultra-centrifuge results using density gradientsto separate sub populations of mitochondria. Other work showed that mitochondria from the liver cells of senescent rats were more susceptible to osmotic shock than their younger counterparts and showed higher State 4 respiration rates.

I speculated then that mega-mitochondria with their evident lack of cristae had a smaller total surface area of the inner membrane leading to a smaller overall electrical capacitance. I coupled this idea with the facts that: mitochondrial membranes become more fragile with age and showed a greater State 4 respiration indicating a degree of uncoupled respiration.

I attributed significance to the idea of lower mitochondrial electrical capacitance, in that a smaller capacitance would need less charge, in a given time, to reach a threshold trans-membrane potential sufficient to provide the free energy to synthesise ATP. 

A 'leaking' membrane ( charge leakage) that struggled to build sufficient charge in a unit of time would appreciate a smaller capacitance simply to get to the point hat it could generate power.

Fifty years on I think that the above observations provide the basis for a mechanism of mitochondrial intracellular aging.

It can be expressed quite simply:

1) Electrons and protons, as raw materials for charge separation across the inner membrane, are supplied by food substrates in the normal metabolic pathways (as memorised by all undergraduate biochemists). The electrochemical gradient created by charge separation is then 'harvested' using the conventional chemiosmotic paradigm in order to drive the reaction of ADP towards ATP. 

2) There is a threshold voltage across the inner membrane, above which its potential energy can be transduced from electrical to chemical in the form of ATP and below which it can't.

3) The rate at which chemical energy can be drawn off the electrical potential depends on the rate of supply of charge to the membrane less any leakage of charge across the membrane; ie a dynamic 'net-potential' over time.That is to say not just the energy but the 'power' of a mitochondrion.

4) The supply of energy for ATP is buffered,  or smoothed out,  by the capacitance of the mitochondrion's inner membrane in order to givea constant supply ( say during fasting, or cell division ) to the cell.

5) The mitochondria's inner membrane's ability to do work ( ie supply chemical energy to the cell) is reduced by leakage of charge.

6) Charge leakage makes it more difficult to reach the threshold potential, ie it takes longer, and one way of mitigating this is to reduce the capacitance of the mitochondrial membrane ( fewer charges needed ) which in turn reduces the power output of the mitochondrion.

7) Excessive charge leakage leads to depolarisation of the membrane and potentially triggering apoptosis.

My hypothesis is that the aging mitochondrion is characterised by increased membrane leakage and reduced capacitance. Further,I speculate that the leaking, or uncoupling as it is known, is the result of endogenous substances. These uncoupling agents are to me potentailly the source of the mysterious aging clock that ticks within cells.

 It is known that leakier mitochondria can be replaced by more tightly coupled mitochondria for instance when a bat moves from a non-flying juvenile to flying adult. I can imagine a molecular uncoupling mechanism linked to a lifespan clock.

 It will be reversible!